International Union of Basic and Clinical Pharmacology XXX: Calcium-sensing receptor Nomenclature, Pharmacology, and Function

A. Identification and cloning of the calcium-sensing receptor (CaSR)

Ca²⁺ is an essential ion, both intra- and extracellularly in mammals. Intracellular Ca²⁺ (Ca²⁺ _i) is maintained at approximately 100 nM, but rises to low micromolar concentrations upon membrane or endoplasmic reticulum Ca²⁺ channel opening, thus serving as an important second messenger (Brini et al., 2013). Ca²⁺ also functions as a key first messenger via activation of the CaSR (Alexander, et al., 2017; Bikle et al., 2019), which plays a pivotal role in tightly regulating ionized (free) extracellular calcium (Ca²⁺ _o). In human plasma, total calcium (referred to herein as calcium to signify ionized and non-ionized calcium) levels are maintained between 2.1 and 2.6 mM of which roughly half is in an ionized form (Brini et al., 2013).

In the mid 1980s there was significant interest in the mechanisms regulating parathyroid hormone (PTH) release from the parathyroid glands. It was consequently shown that elevated Ca²⁺ _o increased Ca²⁺ _i levels and decreased PTH release (LeBoff et al., 1985; Nemeth et al., 1986). In the following years, elevated Ca²⁺ _o was demonstrated to increase inositol phosphate (IP) and decrease cAMP levels, which led to the suggestion of a cell surface calcium-sensing G protein-coupled receptor (GPCR) (Brown et al., 1987a; Chen et al., 1989; Nemeth and Scarpa, 1986; 1987). Further evidence for the receptor was provided via activation of Ca²⁺-sensitive Cl^- channels in Xenopus oocytes injected with mRNA isolated from bovine parathyroid cells (Racke et al., 1993), which subsequently led to expression cloning of the bovine CaSR (Brown et al., 1993). In isolated parathyroid cells, the cloned bovine CaSR was activated by gadolinium > neomycin > Ca²⁺ _o > Mg²⁺ (in rank order of potency) and signaled through elevation of Ca²⁺ _i, providing strong evidence of the cloned receptor being the long sought CaSR (Brown et al., 1993).

Analyses of the cloned receptor sequence revealed a 1,085 amino acid long protein consisting of a large amino-terminal extracellular domain (ECD) of 613 amino acids comprised of a “venus flytrap” (VFT) domain, which closes upon activation much like the VFT plant, and cysteine-rich domain, a 7-transmembrane (7TM) domain of 250 amino acids and an intracellular carboxy-terminus of 222 amino acids (Brown et al., 1993). The analyses also revealed that the CaSR was homologous to the metabotropic glutamate receptors, which were later shown to form the class C GPCRs together with GABA_B, taste type 1, GPRC6A and a handful of orphan receptors (Wellendorph and Bräuner-Osborne, 2009). The structurally conserved class C GPCR VFT domain is homologous to bacterial periplasmic binding proteins, thus it has been predicted that class C GPCRs arose from fusion of the GPCR 7TM with a periplasmic binding protein (O'Hara et al., 1993). Nucleic acid hybridization techniques quickly led to cloning of the human (Garrett et al., 1995a), rat (Riccardi et al., 1995; Ruat et al., 1995), rabbit (Butters et al., 1997), chicken (Diaz et al., 1997) and shark (Nearing et al., 2002) CaSR orthologs, and genome database mining subsequently suggested that the CaSR is evolutionarily conserved to flies and worms (Bjarnadóttir et al., 2005).

B. General gene structure

The human CASR gene has been mapped to chromosome 3q13.3-21 by fluorescence in situ hybridization (FISH) (Janicic et al., 1995) and linkage analyses (Chou et al., 1992). The human CaSR is encoded by 7 exons, of which exons 2-6 encode the ECD, and exon 7 encodes the 7TM and intracellular carboxy terminus (Pearce et al., 1995; Pollak et al., 1993). Two different 5'-untranslated promotor regions, termed exon 1A and 1B, have been identified in humans (Chikatsu et al., 2000), which both splice with the same site in exon 2. As recently reviewed (Hendy and Canaff, 2016), the promotors and thus CaSR expression are regulated by cis-elements responding to 1,25-dihydroxyvitamin D (1,25(OH)₂D), proinflammatory cytokines, and the transcription factor glial cells missing-2 (GCM2).

Tissue specific splice variants lacking exon 3 (Bradbury et al., 1998) and exon 5 (Oda et al., 1998) have been reported but their function (if any) remains elusive. The exon 5 splice variant is of particular interest as it is functional in growth plate chondrocytes (Rodriguez et al., 2005) despite being non-functional when recombinantly expressed in HEK293 and CHO cells. These latter findings led to an initial underestimation of the role of the CaSR in bone development, as the original exon 5 knockout mouse (Ho et al., 1995) displayed a mild bone phenotype compared to a more severe phenotype in the exon 7 knockout mouse model (Chang et al., 2008).

C. Tissue distribution

mRNA probes and antibodies have revealed that the CaSR is widely expressed both in tissues directly involved in controlling systemic Ca²⁺ _o homeostasis as well as in tissues with other functions. As detailed in Section V, the plasma calcium level is mainly regulated via actions on the parathyroid gland (PTH release), thyroid gland (calcitonin release, although calcitonin in humans is less important than in rodents) and the kidney (production of vitamin 1,25(OH)₂D₃ and regulation of ion excretion), but other tissues such as the bone (release of skeletal Ca²⁺ _o) and small intestine (Ca²⁺ _o absorption) also play a role both via direct CaSR activation and via the PTH, calcitonin and vitamin 1,25(OH)₂D₃ hormones (Brown, 2013; Brown and MacLeod, 2001; Lee et al., 2019). In addition, the CaSR is expressed in a range of tissues not involved in systemic Ca²⁺ _o homeostasis such as the keratinocytes of the skin (Section VE), mammary glands (Section VF), pancreas (Section VG), colon (Section VH), airway smooth muscle and epithelium (Section VI), vascular smooth muscle and endothelium (Section VJ) and the brain (Section VK) where the CaSR regulates a range of (patho)physiological functions.

D. Signal transduction pathways

Some of the key CaSR signaling pathways are shown in Figure 1. The CaSR primarily elicits its functions by coupling to the G_i/o and G_q/11 families of heterotrimeric G proteins to activate intracellular signaling pathways that inhibit PTH synthesis and release from parathyroid cells (Section VA). CaSR activation of G_i/o proteins leads to inhibition of the cAMP synthesizing enzyme, adenylate cyclase, causing a decrease in intracellular cAMP levels (Chang et al., 1998; Kifor et al., 2001). CaSR coupling to G_q/11 is usually considered the primary signaling pathway, which activates phospholipase C (PLC)-β to hydrolyze phosphatidylinositol 4,5-bisphosphate to the second messengers IP₃ and diacylglycerol (DAG) (Brown et al., 1993; Chang et al., 1998). IP₃ triggers release of Ca²⁺ _i from intracellular stores, such as the endoplasmic reticulum, and DAG alone or in combination with Ca²⁺ _i activates protein kinase C (PKC). Cytosolic phospholipase A₂, which is the rate-limiting enzyme in arachidonic acid metabolism, can also be activated by the CaSR-mediated G_q/11 pathway through calmodulin and the Ca²⁺/calmodulin-dependent protein kinase II (Handlogten et al., 2001).

The importance of the G_q/11 pathway in CaSR physiology has been demonstrated by the similarities between selective parathyroid knockout of the genes encoding Gα _q (Gnaq) and Gα ₁₁ (Gna11) in mice, which results in a phenotype with almost all the features of Casr germline knockout mice (Wettschureck et al., 2007). Similarly, human CASR and GNA11 loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia (FHH) types 1 (CASR) and 2 (GNA11) or autosomal dominant hypocalcemia (ADH) types 1 (CASR) or 2 (GNA11), respectively (Nesbit et al., 2013a; Pollak et al., 1993; Pollak et al., 1994) (Section VI).

Studies of CaSR coupling to G_12/13 are limited due to a lack of inhibitors and suitable functional readouts. However, the CaSR activates phospholipase D (PLD) in Madin-Darby canine kidney cells through a G_q/11- and G_i/o-independent pathway involving activation of the Rho family of small GTPases, most likely via G_12/13 coupling (Huang et al., 2004). The G_12/13 pathway is also likely to be the G_q/11- and G_i/o-independent pathway that activates the phosphatidylinositol 4-kinase responsible for the first step in inositol biosynthesis through Rho (Huang et al., 2002). However, CaSR can activate RhoA by a G_q/11 pathway in HEK293 cells (Pi et al., 2002) and PLD by a PKC-dependent mechanism likely mediated by G_q/11 in HEK293 cells and parathyroid cells (Kifor et al., 1997), so it remains unclear whether CaSR also couples to G_12/13 in these cells.

CaSR coupling to G_s and the consequent increase in intracellular cAMP levels activates PKA and stimulates PTH related protein (PTHrP) release in immortalized and malignant breast cells and in the AtT-20 pituitary-derived cell line (Mamillapalli et al., 2008; Mamillapalli and Wysolmerski, 2010) (Section VH). Stimulation of cAMP production is not observed in HEK293 cells recombinantly expressing the CaSR (Thomsen et al., 2012a) and the molecular mechanism for the switch in G protein preference in breast cancer and AtT-20 cells remains unknown.

The CaSR activates several mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun N-terminal kinase (JNK) to regulate PTHrP release, proliferation and other functions (Chattopadhyay et al., 2004; MacLeod et al., 2003; Tfelt-Hansen et al., 2003). ERK1/2 is activated by phosphorylation (pERK1/2) through multiple CaSR-mediated pathways, including parallel G protein-dependent pathways involving either G_q/11 and PKC, or G_i/o and epidermal growth factor receptor transactivation (Kifor et al., 2001; MacLeod et al., 2004; Thomsen et al., 2012a). Ras and phosphatidylinositol 3-kinase are also involved in ERK1/2 activation by the CaSR (Hobson et al., 2003), but it is unclear if this pathway overlaps with the G_q/11 or G_i/o dependent pathways. The CaSR can also activate ERK1/2 through a β-arrestin-dependent and G protein-independent pathway (Thomsen et al., 2012a). Furthermore, an Arg680^3.32Gly (numbering shown in superscript after residue numbers throughout this manuscript is based on Ballesteros-Weinstein numbering assigned in (Ballesteros and Weinstein, 1995) for class A GPCRs and in (Dore et al., 2014) for class C GPCRs) CaSR mutation associated with ADH1 selectively increases β-arrestin dependent ERK1/2 activation, where the mutation is predicted to disrupt an extracellular salt bridge between Arg680^3.32 and Glu767 in the second extracellular loop (ECL) (Gorvin et al., 2018a).

In some cell types, the CaSR stimulates opening of L-type voltage-gated Ca²⁺ channels (Fajtova et al., 1991; McGehee et al., 1997; Muff et al., 1988), and nonselective cation channels including transient receptor potential cation (TRPC) channels (El Hiani et al., 2006; Meng et al., 2014; Ye et al., 1996), although the pathways that couple the CaSR to ion channels are poorly defined.

A. Endogenous and exogenous agonists

B. Endogenous and exogenous allosteric modulators

Allosteric modulators bind to sites that are topographically distinct from the orthosteric binding site and act to either potentiate (positive allosteric modulators, or PAMs), inhibit (negative allosteric modulators, or NAMs) or have no effect on (neutral allosteric ligands, or NALs) the binding or efficacy of the orthosteric agonist. Allosteric modulators may also be agonists (or inverse agonists) in the absence of orthosteric agonists, and can simultaneously act as agonists and PAMs (PAM-agonists). CaSR PAMs have been termed type II calcimimetics, and CaSR NAMs calcilytics.

Small molecule allosteric modulators

A detailed review on the discovery and development of CaSR small molecule drugs has recently been published (Nemeth et al., 2018). Therefore, for the purposes of this review, the focus will be on small molecules for which pharmacological or clinical data is available. To date, all CaSR small molecule binding sites have been localized to the 7TM domain and/or ECLs (Bu et al., 2008; Leach et al., 2016; Miedlich et al., 2004; Petrel et al., 2004; Petrel et al., 2003). These sites are distinct from the predominant Ca²⁺ _o, L-amino acid, or γ-glutamyl binding sites in the ECD (see Section III), thus all small molecule CaSR drugs identified so far are allosteric.

For the majority of small molecule PAMs and NAMs, pharmacological characterization has been based on their ability to potentiate or inhibit a single concentration of Ca²⁺ _o, usually in a Ca²⁺ _i mobilization or IP accumulation assay (see Table 1). This approach provides a measure of modulator potency, which is a composite value of affinity, cooperativity (the magnitude and direction of modulator potentiation or inhibition of the orthosteric agonist) and efficacy (i.e. agonism or inverse agonism). While potency measurements facilitate drug comparisons in a series when in vitro assays are performed under identical conditions, they can be misleading when different assay conditions are employed (e.g. different orthosteric agonist concentrations, different signaling outputs) (Gregory et al., 2018). Therefore, more recent work has quantified PAM and NAM affinity, cooperativity and efficacy values as separate parameters using an operational model of allosterism or an allosteric ternary complex model (Cook et al., 2015; Davey et al., 2012; Diepenhorst et al., 2018; Gregory et al., 2018; Leach et al., 2016; Leach et al., 2013).

Table 1. Representative CaSR agonists or endogenous and small molecule allosteric modulators, and their pharmacological properties.

Ligand	Structure	(Cell type or model, assay)	Potencya or affinityb	Cooperativityc with Ca2+ o	References
Agonists
Ca2+ o	Ca2+	Human, PTH release	pEC50 2.9	NA	(Brown, 1983; 1991; Gregory et al., 2018, 2020; Quinn et al., 1997; Ramirez et al., 1993)
Parathyroid cell, PTH release	pEC50 3.0	NA
HEK293, Ca2+ i	pEC50 2.5 – 3.5	NA
HEK293, Caa2+ i	pKB 3.0	NA
Spermine		HEK293, Ca2+ i	pEC50 3.3 – 4.4	NA	(Gregory et al., 2018; Quinn et al., 1997)
Neomycin		HEK293, Ca2+ i	pEC50 4.4	NA	(McLarnon et al., 2002)
PAMs
L-Trp		HEK293, Ca2+ i	pEC50 2.6	ND	(Conigrave et al., 2000)
Cinacalcet		HEK293, Ca2+ i	pKB 5.9 – 6.7	2.6 – 4.7	(Cook et al., 2015; Davey et al., 2012; Diepenhorst et al., 2018; Leach et al., 2016; Leach et al., 2013)
HEK293, IP1	pKB 6.1	2.6 – 4.8
HEK293, pERK1/2	pKB 5.9 – 6.5	1.3 – 2.9
HEK293, membrane ruffling	pKB 8.1	2.6
HEK293, SRF-RE lucd	pKB 7.1	4.5
NPS R-568		HEK293, Ca2+ i	pKB 6.0 – 6.6	3.0 - 3.9	(Cook et al., 2015; Davey et al., 2012; Gregory et al., 2018; Keller et al., 2018; Lu et al., 2009)
CHO, Aequorin	pKB 6.2	2.7
CHO/HEK293, IP1	pKB 6.2 – 6.8	4.3 - 4.5
HEK293, pERK1/2	pKB 5.6 – 6.6	2.0 – 5.1
HEK293, membrane ruffling	pKB 9.4	1.7
Calindol		HEK293, Ca2+ i	pKB 6.3	5.4	(Cook et al., 2015)
HEK293, IP1	pKB 6.4	4.7
HEK293, pERK1/2	pKB 5.2	8.1
Evocalcet		HEK293, Ca2+ i	pEC50 7.0	ND	(Kawata et al., 2018)
R,R-calcimimetic B		HEK293, Ca2+ i	pKB 7.2	1.9	(Cook et al., 2015)
HEK293, IP1	pKB 7.0	3.2
HEK293, pERK1/2	pKB 7.1	3.0
AC265347		HEK293, Ca2+ i	pKB 6.2 – 6.4	2.5 – 4.3	(Cook et al., 2015; Diepenhorst et al., 2018) (Leach et al., 2016)
HEK293, IP1	pKB 7.3 - 8.0	4.0 – 4.7
HEK293, pERK1/2	pKB 6.1 - 6.7	4.5 – 10
HEK293, SRF-RE luc	pKB 6.2	13
BTU compound 13		HEK293, Ca2+ i	pKB 6.7	3.2	(Diepenhorst et al., 2018)
HEK293, IP1	pKB 7.2	2.9
HEK293, pERK1/2	pKB 6.2	1.2
HEK293, SRF-RE luc	pKB 6.5	17
Etelcalcetide		HEK293, IP1	pEC50 4.6	ND	(Walter et al., 2013)
NAMs
NPS 2143		HEK293, Ca2+ i	pKB 6.2 - 6.7	0.3 – 0.5	(Davey et al., 2012; Leach et al., 2016)
HEK293, pERK1/2	pKB 6.2 - 6.6	0.3 - 0.6
HEK293, membrane ruffling	pKB 7.8	0.3
NPSP795		HEK293, assay not disclosed	pIC50 7.1	ND	(Kumar et al., 2010)
Ronacaleret		HEK293, Ca2+ i	pKB 6.4	0.03	(Josephs et al., 2019)
JTT-305/MK-5442		PC12h, zif luce	pIC50 7.9	ND	(Shinagawa et al., 2011)
ATF936		HEK293, Ca2+ i	pKB 7.6	0.005	(Josephs et al., 2019)
BMS compound 1		HEK293, Ca2+ i	pKB 7.0	0.03	(Josephs et al., 2019)
3H-pyrimidine-4-one compound (R)-2h		HEK293, Ca2+ i	pKB 7.8	0.009	(Josephs et al., 2019)
Benzimidazole compound 40		Hamster fibroblasts, Ca2+ i	pIC50 8.4	ND	(Gerspacher et al., 2010)
Mixed PAM/NAM
Calhex 231		HEK293, Ca2+ i	pKB 6.5	ND	(Gregory et al., 2018)

C. Biased agonism and biased allosteric modulation

Given that the CaSR responds to a diverse array of different ligands, it is unsurprising that the CaSR is subject to biased agonism and biased modulation. Biased agonism is the phenomenon by which distinct ligands stabilize preferred GPCR signaling states, with each state having the potential to stimulate or inhibit discrete subsets of the full repertoire of intracellular signaling pathways that couple to a given receptor (Kenakin and Christopoulos, 2013). This is in contrast to the earlier dogma that all agonists activate the same subsets of GPCR signaling pathways to greater (e.g. full agonists) or lesser (e.g. partial agonists) extents. Similarly, biased modulation arises when an allosteric ligand differentially modulates different agonist-mediated signaling pathways.

For instance, in CaSR-HEK293 cells, Ca²⁺ _o preferentially mediates stimulation of Ca²⁺ _i mobilization over pERK1/2, while spermine preferentially activates pERK1/2 (Thomsen et al., 2012a). Similarly, L-amino acids activate Ca²⁺ _i mobilization and ERK phosphorylation (Lee et al., 2007), and also inhibit cAMP synthesis. However, they are inactive in stimulating PI-PLC and various other signaling events including Rho-dependent actin stress fibre formation (Davies et al., 2006) and CREB phosphorylation (Avlani et al., 2013), and appear to promote Ca²⁺ _i mobilization via a G_12/13 / TRPC1-dependent Ca²⁺ _o-influx pathway (Rey et al., 2006; Rey et al., 2005).

Evidence from FHH patients suggests CaSR bias may arise, in part, from spatial and temporal CaSR signaling patterns. Loss-of-function germline mutations of the AP2S1 gene, which encodes the sigma subunit of the heterotetrameric adaptor-related protein complex-2 (AP2σ), cause FHH type 3 (FHH3) (Hannan et al., 2015a; Nesbit et al., 2013b). AP2σ forms part of the heterotetrameric AP2 that plays a critical role in clathrin-mediated endocytosis. AP2σ mutations increase CaSR cell surface expression yet reduce CaSR signaling, because CaSR residency time in clathrin-coated pits is increased, consequently impairing CaSR G_q/11 signaling from endosomes (Gorvin et al., 2018c). In contrast, G_i/o-mediated signaling is less sensitive to AP2σ mutations. Thus, whereas the plasma-membrane localized CaSR signals via G_q/11 and G_i/o, endosomal CaSRs signal predominantly via G_q/11 (Gorvin et al., 2018c).

It must be noted that many of the studies reporting differential CaSR-mediated pathway activation have not been performed in a systematic manner using identical conditions across assays (e.g. buffers, duration of agonist stimulation etc.), or the same cellular background. Further, bias has not been quantified in these studies. Therefore, it remains to be definitively proven whether biased agonism is truly operative at the CaSR, or whether previous observations were due to observational bias (e.g. different assay conditions, different cell types) or system bias (e.g. the relative efficiency with which the receptor couples to different pathways).

Nonetheless, small molecule allosteric modulators do appear to exhibit true biased modulation at the CaSR. Evidence of biased modulation comes from reversals in the magnitude of cooperativity in different pathways between distinct PAMs or NAMs, or from differences in PAM or NAM affinity for receptor states that couple to different signal transducers. For instance, while cinacalcet and NPS 2143 preferentially potentiate or inhibit, respectively, Ca²⁺ _o-mediated Ca²⁺ _i mobilization over pERK1/2, AC265347 and R,R-calcimimetic B show reversed bias for CaSR-mediated pERK1/2 over Ca²⁺ _i mobilization (Cook et al., 2015; Diepenhorst et al., 2018; Leach et al., 2016). Similarly, AC265347, NPS R-568 and calindol, but not cinacalcet or R,R-calcimimetic B, have a higher functional affinity (i.e. an affinity quantified in a functional assay using an operational model of allosterism (Leach et al., 2007)) for the CaSR state that signals to IP₁ accumulation versus Ca²⁺ _i mobilization (Cook et al., 2015; Diepenhorst et al., 2018), while cinacalcet, NPS R-568 and NPS 2143 all have a higher functional affinity for the CaSR state that couples to membrane ruffling (Davey et al., 2012).

Evidence for small molecule PAM and NAM bias also comes from pharmacochaperone studies, which reveal that while cinacalcet, AC265347 and BTU compound 13 are all PAMs in multiple CaSR-mediated signaling assays, only cinacalcet positively modulates the trafficking of an endosomally-trapped naturally occurring mutant CaSR, rescuing its cell surface expression back to levels comparable to wild type CaSR (Cook et al., 2015; Diepenhorst et al., 2018; Leach et al., 2013). In contrast, while NPS 2143 is a NAM of CaSR signaling, it is a PAM of loss-of-expression mutant receptor trafficking (Leach et al., 2013). This is in contrast to the actions of NPS 2143 at the wild type CaSR, where it reduces CaSR surface expression (Huang and Breitwieser, 2007), suggesting naturally occurring mutations (which cause Ca²⁺ _o homeostasis disorders; see Section VI) may engender bias in CaSR function. Indeed, Ca²⁺ _o-mediated bias towards Ca²⁺ _i mobilization is abolished by some naturally occurring mutations (Leach et al., 2012).

Although the physiological relevance of biased agonism and biased modulation at the CaSR is not at present known, differences in the propensity of CaSR PAMs to cause hypocalcemia could be linked to this phenomenon. For instance, as already mentioned, R,R-calcimimetic B and AC265347 are effective suppressors of PTH release. However, in comparison to cinacalcet, R,R-calcimimetic B and AC265347 demonstrate reduced propensity to cause hypocalcemia in rats successfully treated for severe hyperparathyroidism induced by CKD (R,R-calcimimetic B) or in normal rats (AC265347). The reduced incidence of hypocalcemia with R,R-calcimimetic B and AC265347 is presumably linked, in part, to their lower potency and efficacy for the stimulation of calcitonin secretion versus suppression of PTH release (Henley et al., 2011; Ma et al., 2011). Importantly, although suppression of PTH release has been associated with pERK1/2, calcitonin release is independent of pERK1/2 in rat medullary thyroid carcinoma (MTC) cells (Thomsen et al., 2012b). This highlights differences in the coupling specificity of the CaSR in distinct tissues and is consistent with observations that when compared to cinacalcet, AC265347 and R,R-calcimimetic B show reversed bias for CaSR-mediated pERK1/2 over Ca²⁺ _i mobilization.

Another apparent difference between CaSR PAMs points towards putative clinical advantages for cinacalcet. The CaSR agonist, Sr²⁺, reduces the differentiation of bone resorbing osteoclasts (Bonnelye et al., 2008) and stimulates osteoclast apoptosis (Hurtel-Lemaire et al., 2009) (described in Section V). In cultured osteoclasts differentiated from human CD14+ monocytes, while cinacalcet potentiated Sr²⁺-mediated tartrate-resistant acid phosphatase (TRAP) expression (a marker of osteoclast activity), and robustly inhibited osteoclast-mediated hydroxyapartite artificial bone resorption, AC265347 and BTU compound 13 were without effect in these two assays (Diepenhorst et al., 2018). Although it is not clear whether differences in the biased profile of AC265347 and BTU compound 13 versus cinacalcet are responsible for their distinct PAM activities in osteoclasts, it is interesting that only cinacalcet, and not AC265347 or BTU compound 13 can pharmacochaperone loss-of-function mutant CaSRs potentially via differential stabilization of different conformations of the CaSR. A more detailed understanding of the signaling and trafficking pathways that couple the CaSR to its many physiological responses will aid our understanding of why the CaSR responds to so many endogenous activators, and may facilitate the development of biased compounds with improved tissue-specific effects.

In addition to bias engendered by small molecule allosteric modulators, CaSR autoantibodies that cause acquired hypocalciuric hypercalcemia (AHH) can act as biased allosteric modulators. Biased autoantibodies directed against the CaSR VFT can potentiate IP accumulation, while inhibiting pERK1/2 generation (Makita and Iiri, 2014; Makita et al., 2007), while others inhibit pERK1/2 generation but have no effect on IP accumulation (Pallais et al., 2011). Importantly, cinacalcet corrected the severe hypercalcemia associated with AHH caused by a biased autoantibody (Makita et al., 2019). Taken together, these findings once again highlight how bias and allostery are key features of CaSR (patho)physiology and drug actions.

A. CaSR extracellular domain

A. Phosphorylation and dephosphorylation

PKC-mediated phosphorylation of the CaSR provides a rapid and quickly reversible mechanism for inhibiting receptor activity. Indeed, treatment of parathyroid cells with PKC-activating phorbol esters overcomes the inhibitory effect of Ca²⁺ _o on PTH release (Brown et al., 1984; Nemeth et al., 1986). When first cloned, the CaSR was predicted to contain 5 PKC consensus motifs, although 54 serine and threonine residues reside in the receptor’s C-terminal tail and ICLs (Garrett et al., 1995a). However, the key inhibitory phosphorylation site is Thr888 in the C-terminal tail (Bai et al., 1998b). Thr888 is most likely phosphorylated by PKCα (Young et al., 2014) and dephosphorylated by a calyculin A-sensitive protein phosphatase (McCormick et al., 2010).

The functional importance of inhibitory Thr888 phosphorylation is most apparent with the clinical mutant, Thr888Met, which cannot be phosphorylated. In vitro Thr888Met is a gain-of-function mutant, while it suppresses PTH secretion in vivo resulting clinically in ADH (see Section VIC) (Lazarus et al., 2011). Therefore, CaSR phosphorylation contributes significantly to CaSR activity in vivo and thus to the overall control of PTH secretion and Ca²⁺ _o homeostasis (reviewed in (Conigrave and Ward, 2013)).

The non-phosphorylatable mutation, Thr888Val, also produced a significant gain-of-function, which was not further enhanced by co-mutation of the other 4 predicted PKC sites (Bai et al., 1998b). However, PKC inhibition at the wild-type CaSR resulted in a greater gain-of-function than produced at the Thr888Val mutant, thus it appeared likely that another unknown site may be phosphorylated in tandem with Thr888. However, the identity of this site has remained elusive. Interestingly, in mGlu₅ the key PKC phosphorylation site, Ser839 (Kim et al., 2005), aligns not with Thr888 in the CaSR but with Ser875, a residue not originally predicted to be phosphorylated by PKC (Garrett et al., 1995a). Intriguingly, current data indicates removal of this putative phosphorylation site from the CaSR (Ser875Ala) also produces a gain-of-function, similar to that of Thr888Ala, while a phosphomimetic mutation at this site (Ser875Asp) produces a loss-of-function (Binmahfouz et al., 2019b). The double Ser875Ala plus Thr888Ala mutant exhibits a greater gain-of-function than Ser875Ala alone and concomitant PKC inhibition exerts no further signal enhancement. Thus, Ser875 is most likely the second major inhibitory PKC site in the CaSR (Binmahfouz et al., 2019).

Ca²⁺ _o induces biphasic concentration-dependent phosphorylation of Thr888 in CaSR-HEK cells, with 0.5 – 2.5 mM Ca²⁺ _o eliciting increased Thr888 phosphorylation after 10-mins, whereas 2.5 – 5 mM Ca²⁺ _o decreases phosphorylation apparently by activating a calyculin A-sensitive protein phosphatase (McCormick et al., 2010). The decrease in Thr888 phosphorylation mediated by 2.5 – 5 mM Ca²⁺ _o occurs at the same Ca²⁺ _o concentrations that elicit sustained as opposed to oscillatory Ca²⁺ _i mobilization. Consistent with this, the Thr888Ala mutant is not only gain-of-function but also exhibits less oscillatory and more sustained Ca²⁺ _i mobilization, as does the wild-type CaSR when co-treated with a PKC inhibitor (Davies et al., 2007). Furthermore, PKC-dependent phosphorylation of Thr888 attenuates L-amino acid dependent signaling in a manner similar to its effect on Ca²⁺ _o (Bai et al., 1998b; McCormick et al., 2010). Since PKC-mediated Thr888 phosphorylation is thus a critical regulator of CaSR function, differential CaSR phosphorylation could provide a mechanism to permit biased signaling in different cells or in response to various agonists.

CaSR signaling can also be modulated by the GPCR kinases (GRKs). Specifically, overexpression of GRK 2 and 3 decreases CaSR-induced IP formation in a HEK-derived cell-line by >70% (Lorenz et al., 2007). Mutating GRK2 so that it could no longer bind G_q overcame the inhibitory effect of GRK2 on CaSR signaling, indicating that GRK2 inhibition of CaSR signaling might be caused by sequestering of G_q rather than by phosphorylation of the CaSR. Overexpression of either β-arrestin 1 or β-arrestin 2 partly inhibits CaSR-induced IP production and this effect was abolished by deleting all 5 of the predicted PKC sites as identified by Bai et al. (1998b) (Lorenz et al., 2007).

B. Internalization and agonist-driven insertional signaling (ADIS)

In heterologous expression systems, the CaSR undergoes constitutive internalization (Gorvin et al., 2018c; Mos et al., 2019b; Reyes-Ibarra et al., 2007) and agonist-induced internalization (Lorenz et al., 2007; Nesbit et al., 2013b; Zhuang et al., 2012). Furthermore, CaSR internalization is increased by the CaSR PAM, NPS R-568, and agonist-induced but not constitutive internalization is inhibited by the NAM, NPS 2143 (Mos et al., 2019a). GPCR internalization usually involves desensitization by kinase phosphorylation and subsequent β-arrestin binding followed by recruitment to clathrin-coated pits by β-arrestin and the clathrin binding AP2 heterotetramer (Hanyaloglu and von Zastrow, 2008). As described above, phosphorylation by PKC and GRKs, or β-arrestin recruitment, is involved in CaSR desensitization (Lorenz et al., 2007; Pi et al., 2005b). Similarly, agonist-induced CaSR internalization requires β-arrestin, which is in contrast to the GABA_B and mGlu receptors, which function independently of β-arrestin (Pin and Bettler, 2016). However, constitutive and agonist-induced CaSR internalization is largely independent of G_q/11 and G_i/o in HEK293 cells (Mos et al., 2019a), thus indicating that G protein-mediated activation of PKC is not involved in this cell line. Studies of the internalization mechanisms of endogenously expressed CaSRs in non-recombinant cells are still lacking due to the technical difficulty of performing such experiments.

The CaSR is also predicted to couple directly to AP2s through a dileucine motif in the CaSR C-terminal tail (Nesbit et al., 2013b). Similar to loss-of-function mutations in the CASR or GNA11 genes (Nesbit et al., 2013a; Pollak et al., 1993), mutations that disrupt the CaSR interaction with AP2s reduce the sensitivity of CaSR expressing cells to Ca²⁺ _o (Nesbit et al., 2013b). Similarly, germline mutations of the AP2S1 gene that lead to alteration of Arg15 in AP2s cause FHH3 (Nesbit et al., 2013b), which is clinically the most severe of the three FHH types (Hannan et al., 2015a) (Section VI). AP2s Arg-15 mutations inhibit CaSR internalization (Gorvin et al., 2018c; Nesbit et al., 2013b) and the functional similarity between loss-of-function mutations in the CASR, GNA11 and AP2S1 genes shows a close relationship between internalization and CaSR signaling. This relationship could be explained by reduced resensitization and/or intracellular signaling when internalization is inhibited (Gorvin et al., 2018c; Reyes-Ibarra et al., 2007; Zhuang et al., 2012).

After internalization, GPCRs are either resensitized and recycled to the cell surface or degraded (Hanyaloglu and von Zastrow, 2008). Cell surface expression of CaSR is constant under basal conditions (Reyes-Ibarra et al., 2007; Zhuang et al., 2012), which means constitutively internalized receptors are replaced. In heterologous cells, internalized CaSR is recycled through Rab11a-dependent slow-recycling endosomes (Reyes-Ibarra et al., 2007), to be sorted to lysosomes for degradation (Grant et al., 2011; Zhuang et al., 2012). The CaSR’s C-terminal tail is involved in post-endocytic sorting, as deletion of residues 920-970 increased cell surface expression and reduced colocalization with a lysosomal marker (Zhuang et al., 2012). Similarly, overexpression of associated molecule with the SH3 domain of STAM (AMSH), which interacts with the CaSR C-terminal tail, downregulated cell surface CaSR (Herrera-Vigenor et al., 2006; Reyes-Ibarra et al., 2007).

The interaction of 14-3-3 proteins with an arginine-rich motif in the CaSR C-terminal tail partly retains an intracellular CaSR pool (regulated by Ser899 phosphorylation) (Grant et al., 2015; Grant et al., 2011; Stepanchick et al., 2010), but the CaSR is upregulated at the cell surface upon agonist stimulation via a G_q/11-dependent mechanism called agonist-driven insertional signaling (ADIS) (Gorvin et al., 2018c; Grant et al., 2011). This process involves rapid mobilization of the intracellular pool of receptors to the cell surface and initiation of receptor synthesis to support prolonged upregulation (Grant et al., 2015; Grant et al., 2011). The rapid increase in cell surface receptors is proposed to support the high sensitivity of the CaSR to increases in Ca²⁺ _o.

A. CaSR in the parathyroid glands

CaSR expression appears during parathyroid development in response to key parathyroid determining genes including GCM2 (encoding Gcmb) and SHH (encoding the inhibitory controller, Sonic Hedgehog) (Grevellec et al., 2011). Consistent with a direct connection between Gcm2 and CaSR expression, GCM2 control elements have been identified in the CASR promoters (Canaff et al., 2009) and shRNA directed against GCM2 in parathyroid cell cultures suppressed the protein levels of Gcm2 and the CaSR (Mizobuchi et al., 2009).

The CaSR’s non-redundant roles in Ca²⁺ _o metabolism have been clearly established by the hypercalcemic disorders, neonatal severe hyperparathyroidism (NSHPT) and FHH, and the hypocalcemic disorders, ADH and Bartter’s syndrome type 5. These are discussed together with animal models of loss- and gain-of-function mutations of the CaSR in Section VI.

The CaSR negatively controls parathyroid function by suppressing acute PTH secretion primarily from chief cells (review: (Conigrave, 2016)), inhibiting cell proliferation and thus cell number and gland size (Fan et al., 2018), and reducing PTH gene transcription (review: (Chen and Goodman, 2004)). It also activates the local synthesis, particularly in parathyroid oxyphil cells, of 1,25-dihydroxyvitamin D₃ (Ritter et al., 2012), a recognized inhibitor of PTH synthesis. The CaSR’s effects on cell proliferation are particularly noticeable in the context of primary hyperparathyroidism (e.g., due to adenomatous disease) or hyperplasia in the context of CKD. Interestingly, in parathyroid adenoma and CKD, cellular CaSR expression is reduced (Kifor et al., 1996). Nonetheless, in CKD patients and in rat models of secondary hyperparathyroidism, sustained treatment with cinacalcet suppresses parathyroid gland size as well as serum PTH levels (Colloton et al., 2005; Yamada et al., 2015). Similarly, exposure of parathyroid cells to cinacalcet in vitro suppresses proliferation and promotes apoptosis (Tatsumi et al., 2013).

The parathyroid CaSR continuously monitors the Ca²⁺ _o concentration as well as various other stimuli that affect CaSR function, including the plasma levels of L-amino acids (Conigrave et al., 2004), pH (Campion et al., 2015), ionic strength (Quinn et al., 1998), and, perhaps, locally generated polyamines (Quinn et al., 1997) (see Section II). CaSR activity in the parathyroid glands is resistant to desensitization, in part due to efficient receptor recycling, as well as a large intracellular receptor pool that undergoes a high rate of trafficking from the endoplasmic reticulum and Golgi to the plasma membrane (reviews: (Breitwieser, 2013; Ray, 2015)). Whether ADIS operates in parathyroid glands is unknown, but the CaSR interacts with a signaling assembly dependent on caveolin-1 (Kifor et al., 1998) and undergoes AP2s-regulated endocytosis (Gorvin et al., 2018c; Nesbit et al., 2013b).

K. CaSR in the brain

For a comprehensive review of all evidence for CaSR function in the brain, readers are directed to a recent review (Giudice et al., 2019).

While the role of the CaSR in human brain requires validation, the CaSR is expressed throughout the rat brain, with particular abundance in the hippocampus, striatum, cerebellum, pituitary and olfactory bulb (Ruat et al., 1995). However, CaSR expression can change with developmental age (Vizard et al., 2008), supporting a role for the CaSR in brain development. For instance, rat CaSR expression increases in fetal oligodendrocyte precursor cells and postnatal immature oligodendrocytes during myelination of nerve axons, but expression declines in mature oligodendrocytes (Chattopadhyay et al., 2008; Chattopadhyay et al., 1998; Ferry et al., 2000).

While hyperparathyroidism and consequent early lethality resulting from global Casr ablation precludes determination of the role of the CaSR in brain development, concomitant Casr and PTH ablation prevents hyperparathyroidism, and mice survive to adulthood (Kos et al., 2003). In brains of Casr^-/-/Pth^-/- mice, neuron and glial cell differentiation markers were reduced after birth, while differentiation of neural stem cells from Casr^-/- mice was delayed (Liu et al., 2013). These mice also had reduced numbers of gonadotropin-releasing hormone positive neurons in the hypothalamus. These findings suggest a role for the CaSR in neuron and glial cell differentiation.

To elucidate region-specific CaSR brain functions, hippocampus-specific Casr ablation 3 weeks post birth has been undertaken (Kim et al., 2014). While mice did not display an obvious phenotype under normal conditions, they were protected from hippocampal neuronal damage in response to ischemia-induced injury, which mimics injury sustained during cardiac arrest or stroke. In line with these findings, hypoxia increases CaSR expression in rat hippocampal neurons in vivo and in vitro (Bai et al., 2015), but neuroprotection from ischemia is blocked when the related class C GPCR, GABA_BR1, was also ablated (Kim et al., 2014). This may be explained by findings of an increase in CaSR expression in hippocampal neurons in culture upon suppression of GABA_BR1 levels (Chang et al., 2007), which is also observed in cortical neurons of mice who have experienced controlled cortical impact as a model for traumatic brain injury (Kim et al., 2013). In support of a role for the CaSR in the hippocampus, in rat hippocampal neurons from wild type but not Casr^-/- mice, CaSR activation opens nonselective cation channels (Ye et al., 1997b). Similarly, transfection of a dominant-negative Arg185Gln mutant CaSR into pyramidal neurons of hippocampal brain slice cultures resulted in significantly shorter and less complex dendritic branching (Vizard et al., 2008). Taken together, these studies suggest that CaSR NAMs could be neuroprotective.

In addition to neuroprotective effects upon brain injury, inhibition of brain CaSRs may afford neuroprotection in Alzheimer’s disease. The first evidence for a possible role of the CaSR in Alzheimer’s disease came from a study that demonstrated activation of nonselective cation channels in cultured hippocampal pyramidal neurons from wild type rats and mice, but not from Casr^-/- mice (Ye et al., 1997a). While additional studies have since suggested β-amyloid proteins activate the CaSR (Conley et al., 2009; Dal Pra et al., 2014), these findings warrant further validation. Nonetheless, CaSR expression is increased in the hippocampus of an Alzheimer’s disease mouse model (Gardenal et al., 2017) and there is a positive association between CaSR SNPs and Alzheimer’s disease, although only patients who do not habor the Alzheimer’s risk allele encoding ApoE4 (Conley et al., 2009). Further, in human cortical astrocytes and neurons in culture, neurotoxic β-amyloid_25-35 stimulates full-length β-amyloid₄₂ secretion, an effect that is blocked by the CaSR NAM, NPS 2143 (Armato et al., 2013; Chiarini et al., 2017b). NPS 2143 also blocked β-amyloid_25-35-mediated GSK-3β activation and subsequent phosphorylation of tau in cultured human astrocytes (Chiarini et al., 2017a).

The CaSR has also been implicated in the etiology of neuroblastoma, brain tumors originating from precursor nerve cells of the sympathetic nervous system. Approximately 98% of neuroblastomas are associated with spontaneous mutations in a variety of genes (Aygun, 2018). Analysis of mRNA from neuroblastoma tumors indicates that while the CaSR is expressed in benign differentiated tumors, epigenetic hypermethylation of the CASR P2 promoter region silences CASR transcription in some aggressive neuroblastomas (Casala et al., 2013; de Torres et al., 2009). Similarly, two non-coding CASR SNPs (rs7652579 and rs1501899) that reduce CaSR expression are present in homo- or heterozygous form in 58% of neuroblastoma tumors, but in only 47% of the general population (Masvidal et al., 2017). In a subset of ganglioneuromas, CASR expression was absent in 4/6 tumors haboring rs7652579 and rs1501899. However, neuroblastoma patients with rs7652579 and rs1501899 SNPs did not have poorer outcomes or survival (Masvidal et al., 2017). In contrast, neuroblastomas with a haplotype SNP in the CASR gene coding region were associated with poorer outcomes, including increased risk of death (Masvidal et al., 2013). Importantly, cinacalcet reduced neuroblastoma tumor growth in immunocompromised mice carrying neuroblastoma xenografts, by inducing ER stress, tumor differentiation and fibrosis, as well as upregulation of the tumor proteins, cancer-testis antigens (Rodriguez-Hernandez et al., 2016).

Finally, approximately 40% of patients haboring ADH1 gain-of-function CASR mutations present with seizures (Gorvin, 2019). While this could be associated with the consequent reduction in serum calcium concentrations, a gain-of-expression CaSR mutation, Arg898Gln, was identified in an idiopathic epilepsy patients who did not have low serum concentrations of calcium or PTH (Kapoor et al., 2008). These findings suggest a possible role for CaSR in neurotransmission, which is supported by numerous in vitro studies suggesting the CaSR regulates synaptic transmission and neuronal activity via activation of nonselective cation channels on presynaptic terminals (reviewed in Jones and Smith, 2016).

A. Loss- and gain-of-function mutations in the CaSR and its signaling partners

Alterations in CaSR signaling, which lead to derangements of mineral homeostasis, can result from: loss-of-function germline mutations of the CASR gene on chromosome 3q21.1, which cause FHH1 and NSHPT; or gain-of-function germline CASR mutations, which lead to ADH1 and Bartter syndrome type V (Table 2, Figure 4) (Hannan et al., 2012; Hannan and Thakker, 2013). In addition, loss- and gain-of-function germline mutations of the GNA11 gene on chromosome 19p13.3, which encodes Gα ₁₁, are associated with FHH2 and ADH2, respectively (Table 2) (Hannan et al., 2016; Nesbit et al., 2013a). Further, loss-of-function germline mutations of the AP2S1 gene on chromosome 19q13.3, which encodes AP2σ, cause FHH3 (Table 2) (Hannan et al., 2015a; Nesbit et al., 2013b).

B. FHH and NSHPT

FHH is a genetically heterogeneous autosomal dominant disorder characterized by lifelong non-progressive elevations of serum calcium concentrations, mild hypermagnesemia, normal or mildly raised serum PTH concentrations and low urinary calcium excretion (Table 2) (Hannan and Thakker, 2013). FHH1 (OMIM #145980) accounts for ~65% of all FHH cases and is usually an asymptomatic disorder. It has been associated with >150 different CASR mutations (Hannan et al., 2018a). The majority (>85%) of these loss-of-function CASR mutations are heterozygous missense substitutions, which are predominantly located in the VFT of the CaSR ECD, and also in the 7TM (Hannan et al., 2012). These FHH1-associated missense mutations cause a loss-of-function by diminishing the signaling responses of CaSR-expressing cells (Leach et al., 2012), or by reducing CaSR anterograde trafficking and cell-surface expression (Huang and Breitwieser, 2007; White et al., 2009). In addition, FHH1-causing missense mutations may induce biased agonism by switching from a wild type CaSR that preferentially increases Ca²⁺ _i mobilization to mutant receptors that demonstrate equal preference for Ca²⁺ _i and MAPK pathways, or that preferentially act via MAPK (Leach and Gregory, 2017; Leach et al., 2013; Leach et al., 2012). Between 10 to 15% of FHH1 cases are caused by heterozygous deletion, insertion, nonsense and splice-site mutations that lead to nonsense-mediated decay of mRNA and CaSR haploinsufficiency, or truncate the CaSR protein (Hannan et al., 2012). The offspring of two parents with FHH1 can harbor biallelic loss-of-function CASR mutations that cause NSHPT (OMIM #239200), and which is associated with marked hyperparathyroidism that leads to hypercalcemia and bone demineralization causing fractures and respiratory distress (Hannan and Thakker, 2013). Occasionally, biallelic loss-of-function CASR mutations can lead to primary hyperparathyroidism, which presents in adulthood (Table 2) (Hannan et al., 2010). Further, some heterozygous mutations (e.g Arg185Gln) can cause NSHPT due to dominant negative effects on the wild-type CaSR (Bai et al., 1997).

FHH2 (OMIM#145981) is the least common form of FHH and has been reported in four probands to-date (Gorvin et al., 2016; Gorvin et al., 2018b; Nesbit et al., 2013a). FHH2 appears to have a mild clinical presentation with serum adjusted total calcium concentrations usually between 2.55 - 2.80 mM (normal range 2.10 - 2.55 mM). Urinary calcium excretion may be normal or low (Table 2) (Gorvin et al., 2016; Gorvin et al., 2018b; Nesbit et al., 2013a). The GNA11 mutations reported in FHH2 probands consist of three missense substitutions (Thr54Met, Leu135Gln, Phe220Ser) and an in-frame isoleucine deletion (Ile200del) (Gorvin et al., 2016; Gorvin et al., 2018b; Nesbit et al., 2013a). All of these mutations impair CaSR signaling responses, and are located within key domains of the Gα ₁₁ protein (Gorvin et al., 2016; Gorvin et al., 2018b; Nesbit et al., 2013a). Thus, the Ile200del and Phe220Ser mutations are located within the Gα ₁₁ GTPase domain and are predicted to diminish the interaction of Gα ₁₁ with the CaSR or PLC, respectively (Gorvin et al., 2018b; Nesbit et al., 2013a). In contrast, the Leu135Gln mutation is situated within the PLC-interacting portion of the Gα ₁₁ helical domain, and the Thr54Met mutation is located at the interface between the helical and GTPase domains, and may potentially affect GTP binding (Gorvin et al., 2016; Nesbit et al., 2013a).

FHH3 (OMIM#600740) has been reported in >60 FHH probands and has a more marked clinical phenotype than FHH1. Thus, FHH3 is associated with significant elevations of serum calcium and magnesium, and also a significantly reduced urinary calcium excretion compared to FHH1 (Table 2) (Hannan et al., 2015a; Vargas-Poussou et al., 2016). In addition, hypercalcemic symptoms, low bone mineral density and alterations in cognitive function have been described in some FHH3 patients (Hannan et al., 2015a; McMurtry et al., 1992). Nearly all FHH3 cases are caused by a missense mutation of the AP2σ Arg15 residue (Arg15Cys, Arg15His or Arg15Leu) (Fujisawa et al., 2013; Hannan et al., 2015a; Hendy et al., 2014; Hovden et al., 2017; Howles et al., 2016; Nesbit et al., 2013b; Vargas-Poussou et al., 2016). In addition, a genotype-phenotype correlation has been observed at the AP2σ Arg15 residue with the Arg15Leu mutation being associated with significant increases in serum calcium and an earlier age of presentation compared to patients harboring the Arg15Cys or Arg15His AP2σ mutations (Hannan et al., 2015a; Hovden et al., 2017). The AP2σ subunit forms part of the heterotetrameric AP2 complex, which is involved in clathrin-mediated endocytosis (Kelly et al., 2008) and the FHH3-causing AP2σ Arg15 mutations have been shown to reduce CaSR endocytosis and impair endosomal signaling from the internalized CaSR (Gorvin et al., 2018c). However, given the role of AP2 in clathrin-mediated endocytosis, it remains to be established whether phenotypic observations such as cognitive deficits in FHH3 are attributable to CaSR dysregulation, or potentially due to alterations in the endocytosis of other plasma membrane proteins.

C. ADH and Bartter’s syndrome V

ADH is comprised of two genetically distinct variants, designated ADH1 and 2, which are caused by germline gain-of-function mutations of the CaSR and Gα ₁₁, respectively (Table 2) (Hannan et al., 2016). ADH1 (OMIM#601198) is characterized by mild-to-moderate hypocalcemia in association with mild hypomagnesemia, hyperphosphatemia, and serum PTH concentrations that are usually detectable but within the lower half of the reference range (Nesbit et al., 2013a). Patients with ADH1 have significantly increased urinary calcium excretion compared to hypoparathyroid patients (Yamamoto et al., 2000), and ~10% of ADH1 patients have an absolute hypercalciuria (Nesbit et al., 2013a). Some patients with ADH1 may have ectopic calcifications and/or elevations in bone mineral density (BMD) (Pearce et al., 1996), and patients with a severe gain-of-function CaSR mutation may also develop a Bartter syndrome (referred to as Bartter syndrome type V) (Table 2), which is characterized by renal salt wasting leading to volume depletion, hyper-reninemic hyperaldosteronism and hypokalemic alkalosis (Watanabe et al., 2002). Over 90 different ADH1-causing CaSR mutations have been reported (Hannan et al., 2016; Hannan and Thakker, 2013) and around 95% of these are heterozygous missense substitutions, whereas ~5% are in frame or frameshift insertion or deletion mutations (Hannan et al., 2012). ADH1 mutations cluster within the second loop of the VFT domain (residues 116-136), which contributes to the dimeric CaSR interface (Geng et al., 2016) (Figure 4). A second ADH1 mutational hotspot is located in a region that encompasses transmembrane helices 6 and 7, and the intervening third ECL of the CaSR (residues 819-837) (Hannan et al., 2016). This transmembrane region may participate in a network of interactions with other transmembrane helices (Dore et al., 2014), thereby causing the CaSR to adopt an inactive conformational state.

ADH2 (OMIM#615361) (Table 2) has been reported in seven probands (Li et al., 2014a; Mannstadt et al., 2013; Nesbit et al., 2013a; Piret et al., 2016; Tenhola et al., 2016). ADH2 patients generally have mild-to-moderate hypocalcemia, in keeping with the serum biochemical phenotype of ADH1 (Hannan et al., 2016). However, ADH2 is associated with a milder urinary phenotype, with significantly reduced urinary calcium excretion compared to ADH1 (Li et al., 2014a). Moreover, short stature caused by postnatal growth insufficiency has been reported in two ADH2 kindreds (Li et al., 2014a; Tenhola et al., 2016). ADH2-causing mutations all comprise missense substitutions (Arg60Cys, Arg60Leu, Arg181Gln, Ser211Trp, Val340Met and Phe341Leu), which enhance CaSR-mediated signaling responses, consistent with a gain-of-function (Li et al., 2014a; Nesbit et al., 2013a; Piret et al., 2016). ADH2-causing mutations cluster at the interface between the Gα ₁₁ helical and GTPase domains (Piret et al., 2016), and may enhance the exchange of GDP and GTP, thereby leading to G protein activation. ADH2 mutations also affect the C-terminal portion of the Gα ₁₁ protein, which facilitates G protein-GPCR coupling (Piret et al., 2016).

D. Animal models of genetic diseases

Mouse models for FHH, NSHPT and ADH have been generated using gene knockout and knock-in techniques, and also by using chemical mutagenesis (Piret and Thakker, 2011).

FHH/NSHPT mouse models. A mouse model lacking the CaSR was generated by replacing part of exon 5 with a neomycin resistance gene (Ho et al., 1995). Mice harboring this germline heterozygous CaSR deletion (Casr^+/-) had mild hypercalcemia and hypocalciuria, similar to FHH1 patients, whereas, mice with a homozygous CaSR deletion (Casr ^-/-) had a phenotype resembling NSHPT, with parathyroid hyperplasia, severe hypercalcemia, bone abnormalities and retarded growth (Ho et al., 1995). The Casr ^-/- mice died within the first 30 days of life (Ho et al., 1995), which was attributed to severe hyperparathyroidism. In support of this, correction of the hyperparathyroidism by the additional germline ablation of the Pth or Gcm2 genes, rescued the early lethality and bone demineralization in Casr ^-/- mice (Kos et al., 2003; Tu et al., 2003). The importance of the parathyroid CaSR in the pathogenesis of NSHPT has been further highlighted by mice harboring a parathyroid-specific ablation of the CaSR, which developed severe hypercalcemia and hyperparathyroidism (Chang et al., 2008; Fan et al., 2018). In contrast, mice with a kidney-specific ablation of the CaSR do not have alterations in serum calcium or PTH, but are hypocalciuric, and these findings support an independent role of the kidney CaSR in the regulation of urinary calcium excretion (Toka et al., 2012).

A mouse model for FHH2 has been generated by chemical mutagenesis using the N-ethyl-N-nitrosourea (ENU) alkylating agent (Howles et al., 2017). The mutant mice harbor a germline loss-of-function Gna11 mutation, Asp195Gly (D195G) (Howles et al., 2017). Heterozygous (Gna11^+/195G) mice have mild hypercalcemia and normal plasma PTH concentrations (Howles et al., 2017). Homozygous (Gna11^195G/195G) mice have significantly increased plasma calcium and PTH concentrations compared to Gna11^+/195G and wild type mice (Howles et al., 2017). However, Gna11^195G/195G mice do not have growth retardation, bone demineralization or early lethality to suggest an NSHPT phenotype (Howles et al., 2017). Thus, these studies indicate that the loss-of-function D195G Gα ₁₁ mutation is associated with a mild calcitropic phenotype. Furthermore, the Gna11^+/195G and Gna11^195G/195G mice have no alterations in urinary calcium excretion (Howles et al., 2017), which suggests that Gα ₁₁ may not play a major role in the renal handling of calcium.

ADH mouse models. Three different ADH1 mouse models have been reported (Dong et al., 2015; Hough et al., 2004b). Nuf mice (described in Section VG) was generated by chemical mutagenesis using the isopropyl methane sulfonate (iPMS) alkylating agent (Hough et al., 2004a). Heterozygous and homozygous Nuf mice have hypocalcemia, hyperphosphatemia, reduced plasma PTH concentrations, and ectopic calcifications caused by a germline gain-of-function CaSR mutation, Leu723Gln (Hough et al., 2004a). Two knock-in mouse models, which harbor ADH1-causing germline Cys129Ser or Ala843Glu gain-of-function CaSR mutations have also been generated (Dong et al., 2015). Homozygous mutant knock-in mice exhibited embryonic or perinatal lethality, whereas heterozygous knock-in mice have hypocalcemia, hyperphosphatemia, reduced plasma PTH, hypercalciuria and renal calcifications, consistent with the phenotype of ADH1 patients (Dong et al., 2015).

Two mouse models for ADH2 have been described (Gorvin et al., 2017; Roszko et al., 2017). One mouse model, which is known as Dark skin 7 (Dsk7), was generated by ENU chemical mutagenesis (Gorvin et al., 2017), and harbors a germline gain-of-function Gα ₁₁ mutation, Ile62Val, whilst the other ADH2 mouse model was generated by CRISPR-Cas9 gene editing and harbors a human ADH2-causing germline Gα ₁₁ mutation, Arg60Cys (Roszko et al., 2017). Both of these ADH2 mouse models have hypocalcemia, hyperphosphatemia, reduced plasma PTH and normocalciuria in association with increased skin pigmentation (Gorvin et al., 2017; Roszko et al., 2017).

E. Therapeutic interventions – successes and failures

CaSR PAMs represent a targeted therapy for symptomatic forms of FHH (Hannan et al., 2018b), and potentiate the signaling responses of cells expressing FHH-associated CaSR, Gα ₁₁ or AP2σ mutant proteins in vitro (Table 3) (Babinsky et al., 2016; Gorvin et al., 2018b; Howles et al., 2016; Leach et al., 2013; Rus et al., 2008). Furthermore, cinacalcet treatment is effective at decreasing serum calcium concentrations in FHH1 patients and has been reported to improve hypercalcemic symptoms occasionally associated with FHH1 such as anorexia, polydipsia and constipation (Table 3) (Alon and VandeVoorde, 2010; Rasmussen et al., 2011; Sethi et al., 2017). However, the response of NSHPT to cinacalcet is variable and appears to depend on the underlying CASR mutation. Indeed, cinacalcet rectifies the hypercalcemia and hyperparathyroidism in NSHPT patients harboring a heterozygous Arg185Gln CaSR mutation (Fisher et al., 2015; Gannon et al., 2014; Reh et al., 2011), but is less effective for NSHPT patients with biallelic truncating CASR mutations (Table 3) (Atay et al., 2014; Garcia Soblechero et al., 2013), which would be a consequence of the truncated mutant receptor being unable to bind cinacalcet or couple with intracellular signaling proteins (Hannan et al., 2018b). Cinacalcet has also rectified the hypercalcemia in a mouse model for FHH2 (Howles et al., 2017), and ameliorated the hypercalcemia in a symptomatic FHH2 patient (Table 3) (Gorvin et al., 2018b). Furthermore, cinacalcet is an effective therapy for symptomatic hypercalcemia caused by all three types of FHH3-causing Arg15 AP2σ mutations (Table 3) (Howles et al., 2016). However, hypocalcemic symptoms have occurred in a cinacalcet-treated child affected by FHH3 and the chromosome 22q11.2 deletion syndrome (Tenhola et al., 2015). Thus, long-term surveillance is required to detect hypocalcemia in cinacalcet-treated FHH patients (Howles et al., 2016).

CaSR NAMs have been evaluated as a potential targeted therapy for ADH. In vitro studies have demonstrated that NPS 2143 normalizes the signaling responses associated with gain-of-function CASR and GNA11 mutations, which cause ADH1 and ADH2, respectively (Table 3) (Babinsky et al., 2016; Hannan et al., 2015b; Leach et al., 2013; Letz et al., 2010). However, NPS 2143 is less effective for gain-of-function mutations causing Bartter syndrome type V (Leach et al., 2013; Letz et al., 2010). In contrast, the quinazolinone-derived NAMs rectify gain-of-function CASR mutations that cause Bartter syndrome V (Table 3) (Letz et al., 2014). CaSR NAMs have also been characterized in vivo, and single-dose studies have demonstrated that NPS 2143 significantly increases circulating concentrations of calcium and PTH in ADH1 and ADH2 mouse models (Table 3) (Gorvin et al., 2017; Hannan et al., 2015b; Roszko et al., 2017). In addition, repetitive dosing studies have shown that the NAM, JTT-305/MK-5442, prevents the occurrence of nephrocalcinosis in mouse models of ADH1 (Dong et al., 2015). Furthermore, the NAM, NPSP795, has been administered to five ADH1 patients in a phase IIa clinical trial, and increased plasma PTH concentrations and reduced urinary calcium excretion (Table 3) (Roberts et al., 2019). However, circulating calcium concentrations were not altered in these patients, and the optimal dosing regimen of NPSP795 for ADH remains to be established.

1. Aggarwal A, Prinz-Wohlgenannt M, Groschel C, Tennakoon S, Meshcheryakova A, Chang W, Brown EM, Mechtcheriakova D, Kallay E. The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell-like phenotype in the colon. Mol Cancer. 2015;14:61. doi: 10.1186/s12943-015-0330-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Aggarwal A, Schulz H, Manhardt T, Bilban M, Thakker RV, Kallay E. Expression profiling of colorectal cancer cells reveals inhibition of DNA replication licensing by extracellular calcium. Biochim Biophys Acta. 2017;1864:987–996. doi: 10.1016/j.bbamcr.2017.01.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, et al. The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. 2017;174 Suppl 1:S17–S129. doi: 10.1111/bph.13878. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Al-Dujaili SA, Koh AJ, Dang M, Mi X, Chang W, Ma PX, McCauley LK. Calcium sensing receptor function supports osteoblast survival and acts as a co-factor in PTH anabolic actions in bone. J Cell Biochem. 2016;117:1556–1567. doi: 10.1002/jcb.25447. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Alam MU, Kirton JP, Wilkinson FL, Towers E, Sinha S, Rouhi M, Vizard TN, Sage AP, Martin D, Ward DT, Alexander MY, et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res. 2009;81:260–268. doi: 10.1093/cvr/cvn279. [DOI] [PubMed] [Google Scholar]
6. Alamshah A, Spreckley E, Norton M, Kinsey-Jones JS, Amin A, Ramgulam A, Cao Y, Johnson R, Saleh K, Akalestou E, Malik Z, et al. L-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents. Int J Obes (Lond) 2017;41:1693–1701. doi: 10.1038/ijo.2017.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Alexander ST, Hunter T, Walter S, Dong J, Maclean D, Baruch A, Subramanian R, Tomlinson JE. Critical cysteine residues in both the calcium-sensing receptor and the allosteric activator AMG 416 underlie the mechanism of action. Mol Pharmacol. 2015;88:853–865. doi: 10.1124/mol.115.098392. [DOI] [PubMed] [Google Scholar]
8. Alon US, VandeVoorde RG. Beneficial effect of cinacalcet in a child with familial hypocalciuric hypercalcemia. Pediatr Nephrol. 2010;25:1747–1750. doi: 10.1007/s00467-010-1547-5. [DOI] [PubMed] [Google Scholar]
9. Amino Y, Nakazawa M, Kaneko M, Miyaki T, Miyamura N, Maruyama Y, Eto Y. Structure-CaSR-activity relation of kokumi γ-glutamyl peptides. Chem Pharm Bull (Tokyo) 2016;64:1181–1189. doi: 10.1248/cpb.c16-00293. [DOI] [PubMed] [Google Scholar]
10. Arey BJ, Seethala R, Ma Z, Fura A, Morin J, Swartz J, Vyas V, Yang W, Dickson JK, Jr, Feyen JH. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology. 2005;146:2015–2022. doi: 10.1210/en.2004-1318. [DOI] [PubMed] [Google Scholar]
11. Armato U, Chiarini A, Chakravarthy B, Chioffi F, Pacchiana R, Colarusso E, Whitfield JF, Dal Pra I. Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer’s disease. Biochim Biophys Acta. 2013;1832:1634–1652. doi: 10.1016/j.bbadis.2013.04.020. [DOI] [PubMed] [Google Scholar]
12. Atay Z, Bereket A, Haliloglu B, Abali S, Ozdogan T, Altuncu E, Canaff L, Vilaca T, Wong BY, Cole DE, Hendy GN, et al. Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet. Bone. 2014;64:102–107. doi: 10.1016/j.bone.2014.04.010. [DOI] [PubMed] [Google Scholar]
13. Avlani V, Ma W, Mun H-C, Leach K, Delbridge L, Christopoulos A, Conigrave A. Calcium-sensing receptor-dependent activation of CREB phosphorylation in HEK-293 cells and human parathyroid cells. Am J Physiol Endocrinol Metab. 2013;304:E1097–E1104. doi: 10.1152/ajpendo.00054.2013. [DOI] [PubMed] [Google Scholar]
14. Aygun N. Biological and genetic features of neuroblastoma and their clinical importance. Curr Pediatr Rev. 2018;14:73–90. doi: 10.2174/1573396314666180129101627. [DOI] [PubMed] [Google Scholar]
15. Babinsky VN, Hannan FM, Gorvin CM, Howles SA, Nesbit MA, Rust N, Hanyaloglu AC, Hu J, Spiegel AM, Thakker RV. Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein α-11 mutations causing hypercalcemic and hypocalcemic disorders. J Biol Chem. 2016;291:10876–10885. doi: 10.1074/jbc.M115.696401. [DOI] [PMC free article] [PubMed] [Google Scholar]
16. Babinsky VN, Hannan FM, Ramracheya RD, Zhang Q, Nesbit MA, Hugill A, Bentley L, Hough TA, Joynson E, Stewart M, Aggarwal A, et al. Mutant mice with calcium-sensing receptor activation have hyperglycemia that is rectified by calcilytic therapy. Endocrinology. 2017;158:2486–2502. doi: 10.1210/en.2017-00111. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Babinsky VN, Hannan FM, Youhanna SC, Marechal C, Jadoul M, Devuyst O, Thakker RV. Association studies of calcium-sensing receptor (CaSR) polymorphisms with serum concentrations of glucose and phosphate, and vascular calcification in renal transplant recipients. PloS one. 2015;10:e0119459. doi: 10.1371/journal.pone.0119459. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Bai M, Pearce SH, Kifor O, Trivedi S, Stauffer UG, Thakker RV, Brown EM, Steinmann B. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest. 1997;99:88–96. doi: 10.1172/JCI119137. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Bai M, Trivedi S, Brown EM. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem. 1998a;273:23605–23610. doi: 10.1074/jbc.273.36.23605. [DOI] [PubMed] [Google Scholar]
20. Bai M, Trivedi S, Lane CR, Yang Y, Quinn SJ, Brown EM. Protein kinase C phosphorylation of threonine at position 888 in Ca2+ o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. J Biol Chem. 1998b;273:21267–21275. doi: 10.1074/jbc.273.33.21267. [DOI] [PubMed] [Google Scholar]
21. Bai S, Mao M, Tian L, Yu Y, Zeng J, Ouyang K, Yu L, Li L, Wang D, Deng X, Wei C, Luo Y. Calcium sensing receptor mediated the excessive generation of β-amyloid peptide induced by hypoxia in vivo and in vitro. Biochem Biophys Res Commun. 2015;459:568–573. doi: 10.1016/j.bbrc.2015.02.141. [DOI] [PubMed] [Google Scholar]
22. Ballesteros JA, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein- coupled receptors. In: Stuart CS, editor. Methods in Neurosciences. Academic Press; San Diego: 1995. pp. 366–428. [Google Scholar]
23. Bikle D, Bräuner-Osborne H, Brown EM, Chang W, Conigrave A, Hannan F, Leach K, Riccardi D, Shoback D, Ward DT, Yarova P. Calcium-sensing receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE. 2019;2019(4) doi: 10.2218/gtopdb/F12/2019.4. [DOI] [Google Scholar]
24. Bikle DD, Oda Y, Tu CL, Jiang Y. Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer. J Steroid Biochem Mol Biol. 2015;148:47–51. doi: 10.1016/j.jsbmb.2014.10.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Binmahfouz LS, Centeno PP, Conigrave AD, Ward DT. Identification of serine-875 as an inhibitory phosphorylation site in the calcium-sensing receptor. Mol Pharmacol. 2019;96:204–211. doi: 10.1124/mol.119.116178. [DOI] [PubMed] [Google Scholar]
26. Bjarnadóttir TK, Fredriksson R, Schiöth HB. The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste(1) and other related G protein- coupled receptors. Gene. 2005;362:70–84. doi: 10.1016/j.gene.2005.07.029. [DOI] [PubMed] [Google Scholar]
27. Block GA, Bushinsky DA, Cheng S, Cunningham J, Dehmel B, Drueke TB, Ketteler M, Kewalramani R, Martin KJ, Moe SM, Patel UD, Silver J, Sun Y, Wang H, Chertow GM. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: A randomized clinical trial. JAMA. 2017;317:156–164. doi: 10.1001/jama.2016.19468. [DOI] [PubMed] [Google Scholar]
28. Bohr DF. Vascular smooth muscle: Dual effect of calcium. Science. 1963;139:597–599. doi: 10.1126/science.139.3555.597. [DOI] [PubMed] [Google Scholar]
29. Bonnelye E, Chabadel A, Saltel F, Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008;42:129–138. doi: 10.1016/j.bone.2007.08.043. [DOI] [PubMed] [Google Scholar]
30. Boudot C, Hénaut L, Thiem U, Geraci S, Galante M, Saldanha P, Saidak Z, Six I, Clézardin P, Kamel S, Mentaverri R. Overexpression of a functional calcium-sensing receptor dramatically increases osteolytic potential of MDA-MB-231 cells in a mouse model of bone metastasis through epiregulin-mediated osteoprotegerin downregulation. Oncotarget. 2017;8:56460–56472. doi: 10.18632/oncotarget.16999. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Bradbury RA, Sunn KL, Crossley M, Bai M, Brown EM, Delbridge L, Conigrave AD. Expression of the parathyroid Ca2+-sensing receptor in cytotrophoblasts from human term placenta. J Endocrinol. 1998;156:425–430. doi: 10.1677/joe.0.1560425. [DOI] [PubMed] [Google Scholar]
32. Braga VM, Hodivala KJ, Watt FM. Calcium-induced changes in distribution and solubility of cadherins, integrins and their associated cytoplasmic proteins in human keratinocytes. Cell Adhes Commun. 1995;3:201–215. doi: 10.3109/15419069509081287. [DOI] [PubMed] [Google Scholar]
33. Bräuner-Osborne H, Jensen AA, Sheppard PO, O'Hara P, Krogsgaard-Larsen P. The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain. J Biol Chem. 1999;274:18382–18386. doi: 10.1074/jbc.274.26.18382. [DOI] [PubMed] [Google Scholar]
34. Breitwieser G. The calcium sensing receptor life cycle: trafficking, cell surface expression, and degradation. Best Pract Res Clin Endocrinol Metab. 2013;27:303–313. doi: 10.1016/j.beem.2013.03.003. [DOI] [PubMed] [Google Scholar]
35. Brennan SC, Davies TS, Schepelmann M, Riccardi D. Emerging roles of the extracellular calcium-sensing receptor in nutrient sensing: control of taste modulation and intestinal hormone secretion. Br J Nutr. 2014;111 Suppl 1:S16–22. doi: 10.1017/S0007114513002250. [DOI] [PubMed] [Google Scholar]
36. Brennan TC, Rybchyn MS, Green W, Atwa S, Conigrave AD, Mason RS. Osteoblasts play key roles in the mechanisms of action of strontium ranelate. Brit J Pharmacol. 2009;157:1291–1300. doi: 10.1111/j.1476-5381.2009.00305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Brini M, Ottolini D, Calì T, Carafoli E. Chapter 4. Calcium in Health and Disease. In: Sigel A, Sigel H, Sigel RKO, editors. Interrelations between essential metal ions and human diseases Metal ions in life sciences. Springer; 2013. pp. 81–137. [DOI] [PubMed] [Google Scholar]
38. Broadhead GK, Mun HC, Avlani VA, Jourdon O, Church WB, Christopoulos A, Delbridge L, Conigrave AD. Allosteric modulation of the calcium-sensing receptor by γ-glutamyl peptides: inhibition of PTH secretion, suppression of intracellular cAMP levels, and a common mechanism of action with L-amino acids. J Biol Chem. 2011;286:8786–8797. doi: 10.1074/jbc.M110.149724. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab. 1983;56:572–581. doi: 10.1210/jcem-56-3-572. [DOI] [PubMed] [Google Scholar]
40. Brown EM. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev. 1991;71:371–411. doi: 10.1152/physrev.1991.71.2.371. [DOI] [PubMed] [Google Scholar]
41. Brown EM. Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab. 2013;27:333–343. doi: 10.1016/j.beem.2013.02.006. [DOI] [PubMed] [Google Scholar]
42. Brown EM, Butters R, Katz C, Kifor O, Fuleihan GE. A comparison of the effects of concanavalin-A and tetradecanoylphorbol acetate on the modulation of parathyroid function by extracellular calcium and neomycin in dispersed bovine parathyroid cells. Endocrinology. 1992;130:3143–3151. doi: 10.1210/endo.130.6.1317777. [DOI] [PubMed] [Google Scholar]
43. Brown EM, Enyedi P, Leboff M, Rotberg J, Preston J, Chen C. High extracellular Ca2+ and Mg2+ stimulate accumulation of inositol phosphates in bovine parathyroid cells. FEBS Lett. 1987a;218:113–118. doi: 10.1016/0014-5793(87)81029-3. [DOI] [PubMed] [Google Scholar]
44. Brown EM, Fuleihan GE, Chen CJ, Kifor O. A comparison of the effects of divalent and trivalent cations on parathyroid hormone release, 3’,5’-cyclic-adenosine monophosphate accumulation, and the levels of inositol phosphates in bovine parathyroid cells. Endocrinology. 1990;127:1064–1071. doi: 10.1210/endo-127-3-1064. [DOI] [PubMed] [Google Scholar]
45. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature. 1993;366:575–580. doi: 10.1038/366575a0. [DOI] [PubMed] [Google Scholar]
46. Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev. 2001;81:239–297. doi: 10.1152/physrev.2001.81.1.239. [DOI] [PubMed] [Google Scholar]
47. Brown EM, Redgrave J, Thatcher J. Effect of the phorbol ester TPA on PTH secretion. Evidence for a role for protein kinase C in the control of PTH release. FEBS Lett. 1984;175:72–75. doi: 10.1016/0014-5793(84)80572-4. [DOI] [PubMed] [Google Scholar]
48. Brown EM, Watson EJ, Thatcher JG, Koletsky R, Dawson-Hughes BF, Posillico JT, Shoback DM. Ouabain and low extracellular potassium inhibit PTH secretion from bovine parathyroid cells by a mechanism that does not involve increases in the cytosolic calcium concentration. Metabolism. 1987b;36:36–42. doi: 10.1016/0026-0495(87)90060-6. [DOI] [PubMed] [Google Scholar]
49. Bruce JI, Yang X, Ferguson CJ, Elliott AC, Steward MC, Case RM, Riccardi D. Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem. 1999;274:20561–20568. doi: 10.1074/jbc.274.29.20561. [DOI] [PubMed] [Google Scholar]
50. Bu L, Michino M, Wolf RM, Brooks CL. Improved model building and assessment of the Calcium-sensing receptor transmembrane domain. Proteins. 2008;71:215–226. doi: 10.1002/prot.21685. [DOI] [PubMed] [Google Scholar]
51. Burton DW, Foster M, Johnson KA, Hiramoto M, Deftos LJ, Terkeltaub R. Chondrocyte calcium-sensing receptor expression is up-regulated in early guinea pig knee osteoarthritis and modulates PTHrP, MMP-13, and TIMP-3 expression. Osteoarthr Cartilage. 2005;13:395–404. doi: 10.1016/j.joca.2005.01.002. [DOI] [PubMed] [Google Scholar]
52. Busque SM, Kerstetter JE, Geibel JP, Insogna K. L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells. Am J Physiol Gastrointest Liver Physiol. 2005;289:G664–669. doi: 10.1152/ajpgi.00096.2005. [DOI] [PubMed] [Google Scholar]
53. Butters RR, Jr, Chattopadhyay N, Nielsen P, Smith CP, Mithal A, Kifor O, Bai M, Quinn S, Goldsmith P, Hurwitz S, Krapcho K, Busby J, Brown EM. Cloning and characterization of a calcium-sensing receptor from the hypercalcemic New Zealand white rabbit reveals unaltered responsiveness to extracellular calcium. J Bone Miner Res. 1997;12:568–579. doi: 10.1359/jbmr.1997.12.4.568. [DOI] [PubMed] [Google Scholar]
54. Campion KL, McCormick WD, Warwicker J, Khayat ME, Atkinson-Dell R, Steward MC, Delbridge LW, Mun HC, Conigrave AD, Ward DT. Pathophysiologic changes in extracellular pH modulate parathyroid calcium-sensing receptor activity and secretion via a histidine-independent mechanism. J Am Soc Nephrol. 2015;26:2163–2171. doi: 10.1681/ASN.2014070653. [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Canaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25- dihydroxyvitamin D. J Biol Chem. 2002;277:30337–30350. doi: 10.1074/jbc.M201804200. [DOI] [PubMed] [Google Scholar]
56. Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN. Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism. Hum Mutat. 2009;30:85–92. doi: 10.1002/humu.20827. [DOI] [PubMed] [Google Scholar]
57. Capasso G, Geibel PJ, Damiano S, Jaeger P, Richards WG, Geibel JP. The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule. Kidney Int. 2013;84:277–284. doi: 10.1038/ki.2013.137. [DOI] [PubMed] [Google Scholar]
58. Casala C, Gil-Guinon E, Ordonez JL, Miguel-Queralt S, Rodriguez E, Galvan P, Lavarino C, Munell F, de Alava E, Mora J, de Torres C. The calcium-sensing receptor is silenced by genetic and epigenetic mechanisms in unfavorable neuroblastomas and its reactivation induces ERK1/2-dependent apoptosis. Carcinogenesis. 2013;34:268–276. doi: 10.1093/carcin/bgs338. [DOI] [PubMed] [Google Scholar]
59. Casti A, Orlandini G, Reali N, Bacciottini F, Vanelli M, Bernasconi S. Pattern of blood polyamines in healthy subjects from infancy to the adult age. J Endocrinol Invest. 1982;5:263–266. doi: 10.1007/BF03348334. [DOI] [PubMed] [Google Scholar]
60. Cavaco BM, Canaff L, Nolin-Lapalme A, Vieira M, Silva TN, Saramago A, Domingues R, Rutter MM, Hudon J, Gleason JL, Leite V, Hendy GN. Homozygous calcium-sensing receptor polymorphism R544Q presents as hypocalcemic hypoparathyroidism. J Clin Endocrinol Metab. 2018;103:2879–2888. doi: 10.1210/jc.2017-02407. [DOI] [PubMed] [Google Scholar]
61. Ceglia L, Harris SS, Rasmussen HM, Dawson-Hughes B. Activation of the calcium sensing receptor stimulates gastrin and gastric acid secretion in healthy participants. Osteoporos Int. 2009;20:71–78. doi: 10.1007/s00198-008-0637-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
62. Celli A, Sanchez S, Behne M, Hazlett T, Gratton E, Mauro T. The epidermal Ca(2+) gradient: Measurement using the phasor representation of fluorescent lifetime imaging. Biophysical journal. 2010;98:911–921. doi: 10.1016/j.bpj.2009.10.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
63. Centeno PP, Herberger A, Mun H-C, Tu C, Nemeth EF, Chang W, Conigrave AD, Ward DT. Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat Commun. 2019;10 doi: 10.1038/s41467-019-12399-9. 4693. [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Chang W, Pratt S, Chen TH, Bourguignon L, Shoback D. Amino acids in the cytoplasmic C terminus of the parathyroid Ca2+-sensing receptor mediate efficient cell-surface expression and phospholipase C activation. J Biol Chem. 2001;276:44129–44136. doi: 10.1074/jbc.M104834200. [DOI] [PubMed] [Google Scholar]
65. Chang W, Tu C, Chen TH, Bikle D, Shoback D. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal. 2008;1 doi: 10.1126/scisignal.1159945. ra1. [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Chang W, Tu C, Chen TH, Komuves L, Oda Y, Pratt SA, Miller S, Shoback D. Expression and signal transduction of calcium-sensing receptors in cartilage and bone. Endocrinology. 1999;140:5883–5893. doi: 10.1210/endo.140.12.7190. [DOI] [PubMed] [Google Scholar]
67. Chang W, Tu C, Cheng Z, Rodriguez L, Chen TH, Gassmann M, Bettler B, Margeta M, Jan LY, Shoback D. Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. J Biol Chem. 2007;282:25030–25040. doi: 10.1074/jbc.M700924200. [DOI] [PubMed] [Google Scholar]
68. Chang WH, Pratt S, Chen TH, Nemeth E, Huang ZM, Shoback D. Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera. J Bone Miner Res. 1998;13:570–580. doi: 10.1359/jbmr.1998.13.4.570. [DOI] [PubMed] [Google Scholar]
69. Chappell MD, Li R, Smith SC, Dressman BA, Tromiczak EG, Tripp AE, Blanco MJ, Vetman T, Quimby SJ, Matt J, Britton TC, et al. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4- difluorophenyl)sulfanylmethyl]-4-hydroxy-bicy clo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371.HCl): A potent, metabotropic glutamate 2/3 receptor antagonist with antidepressant-like activity. J Med Chem. 2016;59:10974–10993. doi: 10.1021/acs.jmedchem.6b01119. [DOI] [PubMed] [Google Scholar]
70. Chattopadhyay N, Espinosa-Jeffrey A, Tfelt-Hansen J, Yano S, Bandyopadhyay S, Brown EM, de Vellis J. Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: potential impact on reduced myelin basic protein in CaR-null mice. J Neurosci Res. 2008;86:2159–2167. doi: 10.1002/jnr.21662. [DOI] [PubMed] [Google Scholar]
71. Chattopadhyay N, Yano S, Tfelt-Hansen J, Rooney P, Kanuparthi D, Bandyopadhyay S, Ren XH, Terwilliger E, Brown EM. Mitogenic action of calcium-sensing receptor on rat calvarial osteoblasts. Endocrinology. 2004;145:3451–3462. doi: 10.1210/en.2003-1127. [DOI] [PubMed] [Google Scholar]
72. Chattopadhyay N, Ye CP, Yamaguchi T, Kifor O, Vassilev PM, Nishimura R, Brown EM. Extracellular calcium-sensing receptor in rat oligodendrocytes: expression and potential role in regulation of cellular proliferation and an outward K+ channel. Glia. 1998;24:449–458. [PubMed] [Google Scholar]
73. Chen CJ, Anast CS, Brown EM. High osmolality: a potent parathyroid hormone secretogogue in dispersed parathyroid cells. Endocrinology. 1987;121:958–964. doi: 10.1210/endo-121-3-958. [DOI] [PubMed] [Google Scholar]
74. Chen CJ, Barnett JV, Congo DA, Brown EM. Divalent cations suppress 3’,5’-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide- binding protein in cultured bovine parathyroid cells. Endocrinology. 1989;124:233–239. doi: 10.1210/endo-124-1-233. [DOI] [PubMed] [Google Scholar]
75. Chen R, Goodman W. Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol. 2004;286:F1005–F1011. doi: 10.1152/ajprenal.00013.2004. [DOI] [PubMed] [Google Scholar]
76. Cheng I, Klingensmith ME, Chattopadhyay N, Kifor O, Butters RR, Soybel DI, Brown EM. Identification and localization of the extracellular calcium-sensing receptor in human breast. J Clin Endocrinol Metab. 1998;83:703–707. doi: 10.1210/jcem.83.2.4558. [DOI] [PubMed] [Google Scholar]
77. Cheng SX. Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system. Am J Physiol Gastrointest Liver Physiol. 2012;303:G60–70. doi: 10.1152/ajpgi.00425.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Cheng SX, Lightfoot YL, Yang T, Zadeh M, Tang L, Sahay B, Wang GP, Owen JL, Mohamadzadeh M. Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses. FEBS Lett. 2014;588:4158–4166. doi: 10.1016/j.febslet.2014.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
79. Cheng Z, Tu C, Rodriguez L, Chen TH, Dvorak MM, Margeta M, Gassmann M, Bettler B, Shoback D, Chang W. Type B γ-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes. Endocrinology. 2007;148:4984–4992. doi: 10.1210/en.2007-0653. [DOI] [PubMed] [Google Scholar]
80. Chertow GM, Block GA, Correa-Rotter R, Drueke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367:2482–2494. doi: 10.1056/NEJMoa1205624. [DOI] [PubMed] [Google Scholar]
81. Chiarini A, Armato U, Gardenal E, Gui L, Dal Pra I. Amyloid β-exposed human astrocytes overproduce phospho-tau and overrelease it within exosomes, effects suppressed by calcilytic NPS 2143-Further implications for Alzheimer’s therapy. Front Neurosci. 2017a;11:217. doi: 10.3389/fnins.2017.00217. [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Chiarini A, Armato U, Liu D, Dal Pra I. Calcium-sensing receptor antagonist NPS 2143 restores amyloid precursor protein physiological non-amyloidogenic processing in Aβ- exposed adult human astrocytes. Sci Rep. 2017b;7 doi: 10.1038/s41598-017-01215-3. 1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Chikatsu N, Fukumoto S, Takeuchi Y, Suzawa M, Obara T, Matsumoto T, Fujita T. Cloning and characterization of two promoters for the human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas. J Biol Chem. 2000;275:7553–7557. doi: 10.1074/jbc.275.11.7553. [DOI] [PubMed] [Google Scholar]
84. Chou YH, Brown EM, Levi T, Crowe G, Atkinson AB, Arnqvist HJ, Toss G, Fuleihan GE, Seidman JG, Seidman CE. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet. 1992;1:295–300. doi: 10.1038/ng0792-295. [DOI] [PubMed] [Google Scholar]
85. Christopher JA, Aves SJ, Bennett KA, Dore AS, Errey JC, Jazayeri A, Marshall FH, Okrasa K, Serrano-Vega MJ, Tehan BG, Wiggin GR, Congreve M. Fragment and structure- based drug discovery for a class C GPCR: Discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile) J Med Chem. 2015;58:6653–6664. doi: 10.1021/acs.jmedchem.5b00892. [DOI] [PubMed] [Google Scholar]
86. Christopher JA, Orgovan Z, Congreve M, Dore AS, Errey JC, Marshall FH, Mason JS, Okrasa K, Rucktooa P, Serrano-Vega MJ, Ferenczy GG, Keseru GM. Structure-based optimization strategies for G protein-coupled receptor (GPCR) allosteric modulators: A case study from analyses of new metabotropic glutamate receptor 5 (mGlu5) X-ray structures. J Med Chem. 2019;62:207–222. doi: 10.1021/acs.jmedchem.7b01722. [DOI] [PubMed] [Google Scholar]
87. Colloton M, Shatzen E, Miller G, Stehman-Breen C, Wada M, Lacey D, Martin D. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int. 2005;67:467–476. doi: 10.1111/j.1523-1755.2005.67103.x. [DOI] [PubMed] [Google Scholar]
88. Conigrave A. The calcium-sensing receptor and the parathyroid: Past, present, future. Front Physiol. 2016;7(563):1–13. doi: 10.3389/fphys.2016.00563. [DOI] [PMC free article] [PubMed] [Google Scholar]
89. Conigrave AD, Brown EM, Rizzoli R. Dietary protein and bone health: Roles of amino acid–sensing receptors in the control of calcium metabolism and bone homeostasis. Annu Rev Nutr. 2008;28:131–155. doi: 10.1146/annurev.nutr.28.061807.155328. [DOI] [PubMed] [Google Scholar]
90. Conigrave AD, Franks AH, Brown EM, Quinn SJ. L-Amino acid sensing by the calcium- sensing receptor: a general mechanism for coupling protein and calcium metabolism? Eur J Clin Nutr. 2002;56:1072–1080. doi: 10.1038/sj.ejcn.1601463. [DOI] [PubMed] [Google Scholar]
91. Conigrave AD, Hampson DR. Broad-spectrum amino acid sensing by class 3 G-protein coupled receptors. Trends Endocrinol Metab. 2006;17:398–407. doi: 10.1016/j.tem.2006.10.012. [DOI] [PubMed] [Google Scholar]
92. Conigrave AD, Hampson DR. Broad-spectrum amino acid-sensing class C G-protein coupled receptors: molecular mechanisms, physiological significance and options for drug development. Pharmacol Therap. 2010;127:252–260. doi: 10.1016/j.pharmthera.2010.04.007. [DOI] [PubMed] [Google Scholar]
93. Conigrave AD, Mun H-C, Delbridge L, Quinn SJ, Wilkinson M, Brown EM. L-amino acids regulate parathyroid hormone secretion. J Biol Chem. 2004;279:38151–38159. doi: 10.1074/jbc.M406373200. [DOI] [PubMed] [Google Scholar]
94. Conigrave AD, Mun HC, Lok HC. Aromatic L-amino acids activate the calcium-sensing receptor. J Nutr. 2007;137:1524S–1527S. doi: 10.1093/jn/137.6.1524S. discussion 1548S. [DOI] [PubMed] [Google Scholar]
95. Conigrave AD, Quinn SJ, Brown EM. L-amino acid sensing by the extracellular Ca2+- sensing receptor. Proc Natl Acad Sci. 2000;97:4814–4819. doi: 10.1073/pnas.97.9.4814. [DOI] [PMC free article] [PubMed] [Google Scholar]
96. Conigrave AD, Ward DT. Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways. Best Pract Res Clin Endocrinol Metab. 2013;27:315–331. doi: 10.1016/j.beem.2013.05.010. [DOI] [PubMed] [Google Scholar]
97. Conley YP, Mukherjee A, Kammerer C, DeKosky ST, Kamboh MI, Finegold DN, Ferrell RE. Evidence supporting a role for the calcium-sensing receptor in Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:703–709. doi: 10.1002/ajmg.b.30896. [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Cook AE, Mistry SN, Gregory KJ, Furness SG, Sexton PM, Scammells PJ, Conigrave AD, Christopoulos A, Leach K. Biased allosteric modulation at the CaSR engendered by structurally diverse calcimimetics. Br J Pharmacol. 2015;172:185–200. doi: 10.1111/bph.12937. [DOI] [PMC free article] [PubMed] [Google Scholar]
99. Corbetta S, Lania A, Filopanti M, Vicentini L, Ballare E, Spada A. Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells. J Clin Endocrinol Metab. 2002;87:2201–2205. doi: 10.1210/jcem.87.5.8492. [DOI] [PubMed] [Google Scholar]
100. Courbebaisse M, Diet C, Timsit MO, Mamzer MF, Thervet E, Noel LH, Legendre C, Friedlander G, Martinez F, Prie D. Effects of cinacalcet in renal transplant patients with hyperparathyroidism. Am J Nephrol. 2012;35:341–348. doi: 10.1159/000337526. [DOI] [PubMed] [Google Scholar]
101. Dal Pra I, Armato U, Chioffi F, Pacchiana R, Whitfield JF, Chakravarthy B, Gui L, Chiarini A. The Aβ peptides-activated calcium-sensing receptor stimulates the production and secretion of vascular endothelial growth factor-A by normoxic adult human cortical astrocytes. Neuromolecular Med. 2014;16:645–657. doi: 10.1007/s12017-014-8315-9. [DOI] [PubMed] [Google Scholar]
102. Davey AE, Leach K, Valant C, Conigrave AD, Sexton PM, Christopoulos A. Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology. 2012;153:1232–1241. doi: 10.1210/en.2011-1426. [DOI] [PubMed] [Google Scholar]
103. Davies SL, Gibbons CE, Vizard T, Ward DT. Calcium-sensing receptor induces rho kinase-mediated actin stress fiber assembly and altered cell morphology though not in response to aromatic amino acids. Am J Physiol Cell Physiol. 2006;290:1543–1551. doi: 10.1152/ajpcell.00482.2005. [DOI] [PubMed] [Google Scholar]
104. Davies SL, Ozawa A, McCormick WD, Dvorak MM, Ward DT. Protein kinase C- mediated phosphorylation of the calcium-sensing receptor is stimulated by receptor activation and attenuated by calyculin-sensitive phosphatase activity. J Biol Chem. 2007;282:15048–15056. doi: 10.1074/jbc.M607469200. [DOI] [PubMed] [Google Scholar]
105. Dawson-Hughes B. Calcium and protein in bone health. Proc Nutr Soc. 2003;62:505–509. doi: 10.1079/pns2003267. [DOI] [PubMed] [Google Scholar]
106. de Torres C, Beleta H, Diaz R, Toran N, Rodriguez E, Lavarino C, Garcia I, Acosta S, Sunol M, Mora J. The calcium-sensing receptor and parathyroid hormone-related protein are expressed in differentiated, favorable neuroblastic tumors. Cancer. 2009;115:2792–2803. doi: 10.1002/cncr.24304. [DOI] [PubMed] [Google Scholar]
107. Deprez P, Temal T, Jary H, Auberval M, Lively S, Guedin D, Vevert JP. New potent calcimietics: II. Discovery of benzothiazole trisubstituted ureas. Bioorg Med Chem. 2013;23:2455–2459. doi: 10.1016/j.bmcl.2013.01.077. [DOI] [PubMed] [Google Scholar]
108. Diakogiannaki E, Pais R, Tolhurst G, Parker HE, Horscroft J, Rauscher B, Zietek T, Daniel H, Gribble FM, Reimann F. Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor. Diabetologia. 2013;56:2688–2696. doi: 10.1007/s00125-013-3037-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
109. Diaz R, Hurwitz S, Chattopadhyay N, Pines M, Yang Y, Kifor O, Einat MS, Butters R, Hebert SC, Brown EM. Cloning, expression, and tissue localization of the calcium-sensing receptor in chicken (Gallus domesticus) Am J Physiol. 1997;273:R1008–1016. doi: 10.1152/ajpregu.1997.273.3.R1008. [DOI] [PubMed] [Google Scholar]
110. Didiuk MT, Griffith DA, Benbow JW, Liu KK, Walker DP, Bi FC, Morris J, Guzman-Perez A, Gao H, Bechle BM, Kelley RM, Yang X, Dirico K, Ahmed S, Hungerford W, DiBrinno J, Zawistoski MP, Bagley SW, Li J, Zeng Y, Santucci S, Oliver R, Corbett M, Olson T, Chen C, Li M, Paralkar VM, Riccardi KA, Healy DR, Kalgutkar AS, Maurer TS, Nguyen HT, Frederick KS. Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists. Bioorg Med Chem Lett. 2009;19:4555–4559. doi: 10.1016/j.bmcl.2009.07.004. [DOI] [PubMed] [Google Scholar]
111. Diepenhorst NA, Leach K, Keller AN, Rueda P, Cook AE, Pierce TL, Nowell C, Pastoureau P, Sabatini M, Summers RJ, Charman WN, Sexton PM, Christopoulos A, Langmead CJ. Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. Br J Pharmacol. 2018;175:4095–4108. doi: 10.1111/bph.14344. [DOI] [PMC free article] [PubMed] [Google Scholar]
112. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology. 1997;138:4607–4612. doi: 10.1210/endo.138.11.5505. [DOI] [PubMed] [Google Scholar]
113. Dong B, Endo I, Ohnishi Y, Kondo T, Hasegawa T, Amizuka N, Kiyonari H, Shioi G, Abe M, Fukumoto S, Matsumoto T. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-in Mice Mimicking Autosomal Dominant Hypocalcemia (ADH) J Bone Miner Res. 2015;30:1980–1993. doi: 10.1002/jbmr.2551. [DOI] [PubMed] [Google Scholar]
114. Dore AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, Tehan B, Weir M, Wiggin GR, Marshall FH. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature. 2014;511:557–562. doi: 10.1038/nature13396. [DOI] [PubMed] [Google Scholar]
115. Dubois-Ferrière V, Brennan T, Dayer R, Rizzoli R, Ammann P. Calcitropic hormones and IGF-I are influenced by dietary protein. Endocrinology. 2011;152:1839–1847. doi: 10.1210/en.2010-1079. [DOI] [PubMed] [Google Scholar]
116. Dufner MM, Kirchhoff P, Remy C, Hafner P, Muller MK, Cheng SX, Tang LQ, Hebert SC, Geibel JP, Wagner CA. The calcium-sensing receptor acts as a modulator of gastric acid secretion in freshly isolated human gastric glands. Am J Physiol Gastrointest Liver Physiol. 2005;289:G1084–1090. doi: 10.1152/ajpgi.00571.2004. [DOI] [PubMed] [Google Scholar]
117. Dvorak MM, Chen TH, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM. Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone. Endocrinology. 2007;148:3156–3163. doi: 10.1210/en.2007-0147. [DOI] [PubMed] [Google Scholar]
118. Dvorak-Ewell MM, Chen TH, Liang N, Garvey C, Liu B, Tu C, Chang W, Bikle DD, Shoback DM. Osteoblast extracellular Ca2+-sensing receptor regulates bone development, mineralization, and turnover. J Bone Miner Res. 2011;26:2935–2947. doi: 10.1002/jbmr.520. [DOI] [PMC free article] [PubMed] [Google Scholar]
119. El Hiani Y, Ahidouch A, Roudbaraki M, Guenin S, Brule G, Ouadid-Ahidouch H. Calcium-sensing receptor stimulation induces nonselective cation channel activation in breast cancer cells. J Membr Biol. 2006;211:127–137. doi: 10.1007/s00232-006-0017-2. [DOI] [PubMed] [Google Scholar]
120. Elajnaf T, Iamartino L, Mesteri I, Muller C, Bassetto M, Mangardt T, Baumgartner-Parzer S, Kallay E, Schepelmann M. Nutritional and pharmacological targeting of the calcium- sensing receptor influences chemically induced colitis in mice. Nutrients. 2019;11 doi: 10.3390/nu11123072. pii: E3072. [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Ellison TI, Smith MK, Gilliam AC, MacDonald PN. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis. J Invest Dermatol. 2008;128:2508–2517. doi: 10.1038/jid.2008.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
122. Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S, Piper PK, Walker AK, Pedersen MH, Nohr MK, Pan J, Sinz CJ, et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab. 2013;2:376–392. doi: 10.1016/j.molmet.2013.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
123. Fajtova VT, Quinn SJ, Brown EM. Cytosolic calcium responses of single rMTC 44-2 cells to stimulation with external calcium and potassium. Am J Physiol. 1991;261:E151–E158. doi: 10.1152/ajpendo.1991.261.1.E151. [DOI] [PubMed] [Google Scholar]
124. Fan GF, Ray K, Zhao XM, Goldsmith PK, Spiegel AM. Mutational analysis of the cysteines in the extracellular domain of the human Ca2+ receptor: effects on cell surface expression, dimerization and signal transduction. FEBS Lett. 1998;436:353–356. doi: 10.1016/s0014-5793(98)01165-x. [DOI] [PubMed] [Google Scholar]
125. Fan Y, Liu W, Bi R, Densmore MJ, Sato T, Mannstadt M, Yuan Q, Zhou X, Olauson H, Larsson TE, Toka HR, et al. Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia. Proc Natl Acad Sci USA. 2018;115:E3749–E3758. doi: 10.1073/pnas.1717754115. [DOI] [PMC free article] [PubMed] [Google Scholar]
126. Feng J, Petersen CD, Coy DH, Jiang JK, Thomas CJ, Pollak MR, Wank SA. Calcium- sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion. Proc Natl Acad Sci USA. 2010;107:17791–17796. doi: 10.1073/pnas.1009078107. [DOI] [PMC free article] [PubMed] [Google Scholar]
127. Ferry S, Traiffort E, Stinnakre J, Ruat M. Developmental and adult expression of rat calcium-sensing receptor transcripts in neurons and oligodendrocytes. Eur J Neurosci. 2000;12:872–884. doi: 10.1046/j.1460-9568.2000.00980.x. [DOI] [PubMed] [Google Scholar]
128. Fetahu IS, Hummel DM, Manhardt T, Aggarwal A, Baumgartner-Parzer S, Kallay E. Regulation of the calcium-sensing receptor expression by 1,25-dihydroxyvitamin D3, interleukin-6, and tumor necrosis factor alpha in colon cancer cells. J Steroid Biochem Mol Biol. 2014;144 Pt A:228–231. doi: 10.1016/j.jsbmb.2013.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
129. Fisher JE, Scott K, Wei N, Zhao JZ, Cusick T, Tijerina M, Karanam B, Duong L, Glantschnig H. Pharmacodynamic responses to combined treatment regimens with the calcium sensing receptor antagonist JTT-305/MK-5442 and alendronate in osteopenic ovariectomized rats. Bone. 2012;50:1332–1342. doi: 10.1016/j.bone.2012.03.004. [DOI] [PubMed] [Google Scholar]
130. Fisher MM, Cabrera SM, Imel EA. Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients. Endocrinol Diabetes Metab Case Rep. 2015;2015 doi: 10.1530/EDM-15-0040. 150040. [DOI] [PMC free article] [PubMed] [Google Scholar]
131. Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Fuerst T, Engelke K, Genant HK. Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women. J Bone Miner Res. 2012;27:255–262. doi: 10.1002/jbmr.554. [DOI] [PubMed] [Google Scholar]
132. Fitzpatrick LA, Dabrowski CE, Cicconetti G, Gordon DN, Papapoulos S, Bone HG, Bilezikian JP. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab. 2011a;96:2441–2449. doi: 10.1210/jc.2010-2855. [DOI] [PubMed] [Google Scholar]
133. Fitzpatrick LA, Smith PL, McBride TA, Fries MA, Hossain M, Dabrowski CE, Gordon DN. Ronacaleret, a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: results of a randomized, double-blinded, placebo-controlled Phase II clinical trial. Bone. 2011b;49:845–852. doi: 10.1016/j.bone.2011.06.017. [DOI] [PubMed] [Google Scholar]
134. Freichel M, Zink-Lorenz A, Holloschi A, Hafner M, Flockerzi V, Raue F. Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion. Endocrinology. 1996;137:3842–3848. doi: 10.1210/endo.137.9.8756555. [DOI] [PubMed] [Google Scholar]
135. Friedman PA. Codependence of renal calcium and sodium transport. Annu Rev Physiol. 1998;60:179–197. doi: 10.1146/annurev.physiol.60.1.179. [DOI] [PubMed] [Google Scholar]
136. Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci USA. 2003;100:2290–2295. doi: 10.1073/pnas.0435715100. [DOI] [PMC free article] [PubMed] [Google Scholar]
137. Fudge NJ, Kovacs CS. Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo. BMC Physiol. 2004;4:5. doi: 10.1186/1472-6793-4-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
138. Fujisawa Y, Yamaguchi R, Satake E, Ohtaka K, Nakanishi T, Ozono K, Ogata T. Identification of AP2S1 mutation and effects of low calcium formula in an infant with hypercalcemia and hypercalciuria. J Clin Endocrinol Metab. 2013;98:E2022–2027. doi: 10.1210/jc.2013-2571. [DOI] [PubMed] [Google Scholar]
139. Fukagawa M, Shimazaki R, Akizawa T, Evocalcet study g Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int. 2018;94:818–825. doi: 10.1016/j.kint.2018.05.013. [DOI] [PubMed] [Google Scholar]
140. Gama L, Wilt SG, Breitwieser GE. Heterodimerization of calcium sensing receptors with metabotropic glutamate receptors in neurons. J Biol Chem. 2001;276:39053–39059. doi: 10.1074/jbc.M105662200. [DOI] [PubMed] [Google Scholar]
141. Gannon AW, Monk HM, Levine MA. Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review. J Clin Endocrinol Metab. 2014;99:7–11. doi: 10.1210/jc.2013-2834. [DOI] [PMC free article] [PubMed] [Google Scholar]
142. Garcia Soblechero E, Ferrer Castillo MT, Jimenez Crespo B, Dominguez Quintero ML, Gonzalez Fuentes C. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. Neonatology. 2013;104:104–108. doi: 10.1159/000350540. [DOI] [PubMed] [Google Scholar]
143. Gardenal E, Chiarini A, Armato U, Dal Pra I, Verkhratsky A, Rodriguez JJ. Increased calcium-sensing receptor immunoreactivity in the hippocampus of a triple transgenic mouse model of Alzheimer’s disease. Front Neurosci. 2017;11:81. doi: 10.3389/fnins.2017.00081. [DOI] [PMC free article] [PubMed] [Google Scholar]
144. Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F. Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J Biol Chem. 1995a;270:12919–12925. doi: 10.1074/jbc.270.21.12919. [DOI] [PubMed] [Google Scholar]
145. Garrett JE, Tamir H, Kifor O, Simin RT, Rogers KV, Mithal A, Gagel RF, Brown EM. Calcitonin-secreting cells of the thyroid gland express an extracellular calcium-sensing receptor gene. Endocrinology. 1995b;136:5202–5211. doi: 10.1210/endo.136.11.7588259. [DOI] [PubMed] [Google Scholar]
146. Geibel J, Sritharan K, Geibel R, Geibel P, Persing JS, Seeger A, Roepke TK, Deichstetter M, Prinz C, Cheng SX, Martin D, Hebert SC. Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction. Proc Natl Acad Sci USA. 2006;103:9390–9397. doi: 10.1073/pnas.0602996103. [DOI] [PMC free article] [PubMed] [Google Scholar]
147. Geibel JP, Hebert SC. The functions and roles of the extracellular Ca2+-sensing receptor along the gastrointestinal tract. Annu Rev Physiol. 2009;71:205–217. doi: 10.1146/annurev.physiol.010908.163128. [DOI] [PubMed] [Google Scholar]
148. Geng Y, Bush M, Mosyak L, Wang F, Fan QR. Structural mechanism of ligand activation in human GABA(B) receptor. Nature. 2013;504:254–259. doi: 10.1038/nature12725. [DOI] [PMC free article] [PubMed] [Google Scholar]
149. Geng Y, Mosyak L, Kurinov I, Zuo H, Sturchler E, Cheng TC, Subramanyam P, Brown AP, Brennan SC, Mun HC, Bush M, et al. Structural mechanism of ligand activation in human calcium-sensing receptor. Elife. 2016;5:e13662. doi: 10.7554/eLife.13662. [DOI] [PMC free article] [PubMed] [Google Scholar]
150. Geng Y, Xiong D, Mosyak L, Malito DL, Kniazeff J, Chen Y, Burmakina S, Quick M, Bush M, Javitch JA, Pin JP, Fan QR. Structure and functional interaction of the extracellular domain of human GABA(B) receptor GBR2. Nat Neurosci. 2012;15:970–978. doi: 10.1038/nn.3133. [DOI] [PMC free article] [PubMed] [Google Scholar]
151. Gerspacher M, Altmann E, Beerli R, Buhl T, Endres R, Gamse R, Kameni-Tcheudji J, Kneissel M, Krawinkler KH, Missbach M, Schmidt A, Seuwen K, Weiler S, Widler L. Penta- substituted benzimidazoles as potent antagonists of the calcium-sensing receptor (CaSR- antagonists) Bioorg Med Chem Lett. 2010;20:5161–5164. doi: 10.1016/j.bmcl.2010.07.016. [DOI] [PubMed] [Google Scholar]
152. Giudice ML, Mihalik B, Dinnyes A, Kobolak J. The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease. Molecules. 2019;24 doi: 10.3390/molecules24142546. pii:E2546. [DOI] [PMC free article] [PubMed] [Google Scholar]
153. Goltzman D, Hendy GN. The calcium-sensing receptor in bone--mechanistic and therapeutic insights. Nat Rev Endocrinol. 2015;11:298–307. doi: 10.1038/nrendo.2015.30. [DOI] [PubMed] [Google Scholar]
154. Gong Y, Hou J. Claudin-14 underlies Ca++-sensing receptor-mediated Ca++ metabolism via NFAT-microRNA-based mechanisms. J Am Soc Nephrol. 2014;25:745–760. doi: 10.1681/ASN.2013050553. [DOI] [PMC free article] [PubMed] [Google Scholar]
155. Goolam MA, Ward JH, Avlani VA, Leach K, Christopoulos A, Conigrave AD. Roles of intraloops-2 and -3 and the proximal C-terminus in signalling pathway selection from the human calcium-sensing receptor. FEBS Lett. 2014;588:3340–3346. doi: 10.1016/j.febslet.2014.07.022. [DOI] [PubMed] [Google Scholar]
156. Gorvin CM. Molecular and clinical insights from studies of calcium-sensing receptor mutations. J Mol Endocrinol. 2019;63:R1–R16. doi: 10.1530/JME-19-0104. [DOI] [PubMed] [Google Scholar]
157. Gorvin CM, Babinsky VN, Malinauskas T, Nissen PH, Schou AJ, Hanyaloglu AC, Siebold C, Jones EY, Hannan FM, Thakker RV. A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate ß-arrestin-biased signaling. Sci Signal. 2018a;11 doi: 10.1126/scisignal.aan3714. pii:eaan3714. [DOI] [PMC free article] [PubMed] [Google Scholar]
158. Gorvin CM, Cranston T, Hannan FM, Rust N, Qureshi A, Nesbit MA, Thakker RV. G- protein subunit-α11 loss-of-function mutation, Thr54Met, causing familial hypocalciuric hypercalcemia type 2 (FHH2) J Bone Miner Res. 2016;31:1200–1206. doi: 10.1002/jbmr.2778. [DOI] [PMC free article] [PubMed] [Google Scholar]
159. Gorvin CM, Hannan FM, Cranston T, Valta H, Makitie O, Schalin-Jantti C, Thakker RV. Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function Gα11 mutation. J Bone Miner Res. 2018b;33:32–41. doi: 10.1002/jbmr.3241. [DOI] [PMC free article] [PubMed] [Google Scholar]
160. Gorvin CM, Hannan FM, Howles SA, Babinsky VN, Piret SE, Rogers A, Freidin AJ, Stewart M, Paudyal A, Hough TA, Nesbit MA, et al. Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight. 2017;2:e91103. doi: 10.1172/jci.insight.91103. [DOI] [PMC free article] [PubMed] [Google Scholar]
161. Gorvin CM, Rogers A, Hastoy B, Tarasov AI, Frost M, Sposini S, Inoue A, Whyte MP, Rorsman P, Hanyaloglu AC, Breitwieser GE, et al. AP2σ mutations impair calcium- sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct G-protein selectivity. Cell Rep. 2018c;22:1054–1066. doi: 10.1016/j.celrep.2017.12.089. [DOI] [PMC free article] [PubMed] [Google Scholar]
162. Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ, Smith BR, Bhatnagar PK, Lago AM, Callahan JF, DelMar EG, Miller MA, et al. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest. 2000;105:1595–1604. doi: 10.1172/JCI9038. [DOI] [PMC free article] [PubMed] [Google Scholar]
163. Graca JA, Schepelmann M, Brennan SC, Reens J, Chang W, Yan P, Toka H, Riccardi D, Price SA. Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney. Am J Physiol Renal Physiol. 2016;310:F518–533. doi: 10.1152/ajprenal.00208.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
164. Grant MP, Cavanaugh A, Breitwieser GE. 14-3-3 Proteins Buffer Intracellular Calcium Sensing Receptors to Constrain Signaling. PloS one. 2015;10:e0136702. doi: 10.1371/journal.pone.0136702. [DOI] [PMC free article] [PubMed] [Google Scholar]
165. Grant MP, Epure LM, Bokhari R, Roughley P, Antoniou J, Mwale F. Human cartilaginous endplate degeneration is induced by calcium and the extracellular calcium- sensing receptor in the intervertebral disc. Eur Cells Mater. 2016;32:137–151. doi: 10.22203/ecm.v032a09. [DOI] [PubMed] [Google Scholar]
166. Grant MP, Stepanchick A, Cavanaugh A, Breitwieser GE. Agonist-driven maturation and plasma membrane insertion of calcium-sensing receptors dynamically control signal amplitude. Sci Signal. 2011;4 doi: 10.1126/scisignal.2002208. ra78. [DOI] [PubMed] [Google Scholar]
167. Gray E, Muller D, Squires PE, Asare-Anane H, Huang GC, Amiel S, Persaud SJ, Jones PM. Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases. J Endocrinol. 2006;190:703–710. doi: 10.1677/joe.1.06891. [DOI] [PubMed] [Google Scholar]
168. Gregory KJ, Giraldo J, Daio J, Christopoulos A, Leach K. Evaluation of operational models of agonism and allosterism at receptors with multiple orthosteric binding sites. Mol Pharmacol. 2020;97:35–45. doi: 10.1124/mol.119.118091. [DOI] [PubMed] [Google Scholar]
169. Gregory KJ, Kufareva I, Keller AN, Khajehali E, Mun HC, Goolam MA, Mason RS, Capuano B, Conigrave AD, Christopoulos A, Leach K. Dual action calcium-sensing receptor modulator unmasks novel mode-switching mechanism. Pharm Trans Sci. 2018;1:96–109. doi: 10.1021/acsptsci.8b00021. [DOI] [PMC free article] [PubMed] [Google Scholar]
170. Grevellec A, Graham A, Tucker AS. Shh signalling restricts the expression of Gcm2 and controls the position of the developing parathyroids. Dev Biol. 2011;353:194–205. doi: 10.1016/j.ydbio.2011.02.012. [DOI] [PubMed] [Google Scholar]
171. Halse J, Greenspan S, Cosman F, Ellis G, Santora A, Leung A, Heyden N, Samanta S, Doleckyj S, Rosenberg E, Denker AE. A phase 2, randomized, placebo-controlled, dose- ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2014;99:E2207–2215. doi: 10.1210/jc.2013-4009. [DOI] [PMC free article] [PubMed] [Google Scholar]
172. Hamano N, Komaba H, Fukagawa M. Etelcalcetide for the treatment of secondary hyperparathyroidism. Expert Opin Pharmacother. 2017;18:529–534. doi: 10.1080/14656566.2017.1303482. [DOI] [PubMed] [Google Scholar]
173. Handlogten ME, Huang CF, Shiraishi N, Awata H, Miller RT. The Ca2+-sensing receptor activates cytosolic phospholipase A2 via a Gqα-dependent ERK-independent pathway. J Biol Chem. 2001;276:13941–13948. doi: 10.1074/jbc.M007306200. [DOI] [PubMed] [Google Scholar]
174. Handlogten ME, Shiraishi N, Awata H, Huang C, Miller RT. Extracellular Ca(2+)- sensing receptor is a promiscuous divalent cation sensor that responds to lead. Am J Physiol Renal Physiol. 2000;279:F1083–1091. doi: 10.1152/ajprenal.2000.279.6.F1083. [DOI] [PubMed] [Google Scholar]
175. Hannan FM, Babinsky VN, Thakker RV. Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. J Mol Endocrinol. 2016;57:R127–142. doi: 10.1530/JME-16-0124. [DOI] [PMC free article] [PubMed] [Google Scholar]
176. Hannan FM, Howles SA, Rogers A, Cranston T, Gorvin CM, Babinsky VN, Reed AA, Thakker CE, Bockenhauer D, Brown RS, Connell JM, et al. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects. Hum Mol Genet. 2015a;24:5079–5092. doi: 10.1093/hmg/ddv226. [DOI] [PMC free article] [PubMed] [Google Scholar]
177. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018a;15:33–51. doi: 10.1038/s41574-018-0115-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
178. Hannan FM, Nesbit MA, Christie PT, Lissens W, Van der Schueren B, Bex M, Bouillon R, Thakker RV. A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia. Clin Endocrinol (Oxf) 2010;73:715–722. doi: 10.1111/j.1365-2265.2010.03870.x. [DOI] [PubMed] [Google Scholar]
179. Hannan FM, Nesbit MA, Zhang C, Cranston T, Curley AJ, Harding B, Fratter C, Rust N, Christie PT, Turner JJ, Lemos MC, et al. Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites. Hum Mol Genet. 2012;21:2768–2778. doi: 10.1093/hmg/dds105. [DOI] [PubMed] [Google Scholar]
180. Hannan FM, Olesen MK, Thakker RV. Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway. Br J Pharmacol. 2018b;175:4083–4094. doi: 10.1111/bph.14086. [DOI] [PMC free article] [PubMed] [Google Scholar]
181. Hannan FM, Thakker RV. Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract Res Clin Endocrinol Metab. 2013;27:359–371. doi: 10.1016/j.beem.2013.04.007. [DOI] [PubMed] [Google Scholar]
182. Hannan FM, Walls GV, Babinsky VN, Nesbit MA, Kallay E, Hough TA, Fraser WD, Cox RD, Hu J, Spiegel AM, Thakker RV. The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing receptor (CaSR) mutation: Relevance to autosomal dominant hypocalcemia type 1 (ADH1) Endocrinology. 2015b;156:3114–3121. doi: 10.1210/en.2015-1269. [DOI] [PMC free article] [PubMed] [Google Scholar]
183. Hanyaloglu AC, von Zastrow M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol. 2008;48:537–568. doi: 10.1146/annurev.pharmtox.48.113006.094830. [DOI] [PubMed] [Google Scholar]
184. Hauache OM, Hu J, Ray K, Spiegel AM. Functional interactions between the extracellular domain and the seven-transmembrane domain in Ca2+ receptor activation. Endocrine. 2000;13:63–70. doi: 10.1385/ENDO:13:1:63. [DOI] [PubMed] [Google Scholar]
185. Hebert SC, Brown EM, Harris HW. Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. J Exp Biol. 1997;200:295–302. doi: 10.1242/jeb.200.2.295. [DOI] [PubMed] [Google Scholar]
186. Hendy GN, Canaff L. Calcium-sensing receptor gene: Regulation of expression. Front Physiol. 2016;7:394. doi: 10.3389/fphys.2016.00394. [DOI] [PMC free article] [PubMed] [Google Scholar]
187. Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BY, Lee BS, Cole DE. Codon Arg15 mutations of the AP2S1 Gene: Common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations. J Clin Endocrinol Metab. 2014;99:E1311–1315. doi: 10.1210/jc.2014-1120. [DOI] [PubMed] [Google Scholar]
188. Henley C, Yang Y, Davis J, Lu JY, Morony S, Fan W, Florio M, Sun B, Shatzen E, Pretorius JK, Richards WG, et al. Discovery of a calcimimetic with differential effects on parathyroid hormone and calcitonin secretion. J Pharmacol Exp Ther. 2011;337:681–691. doi: 10.1124/jpet.110.178681. [DOI] [PubMed] [Google Scholar]
189. Hernandez-Bedolla MA, Carretero-Ortega J, Valadez-Sanchez M, Vazquez-Prado J, ReyesCruz G. Chemotactic and proangiogenic role of calcium sensing receptor is linked to secretion of multiple cytokines and growth factors in breast cancer MDA-MB-231 cells. Biochim Biophys Acta. 2015;1853:166–182. doi: 10.1016/j.bbamcr.2014.10.011. [DOI] [PubMed] [Google Scholar]
190. Herrera-Vigenor F, Hernandez-Garcia R, Valadez-Sanchez M, Vazquez-Prado J, Reyes-Cruz G. AMSH regulates calcium-sensing receptor signaling through direct interactions. Biochem Biophys Res Commun. 2006;347:924–930. doi: 10.1016/j.bbrc.2006.06.169. [DOI] [PubMed] [Google Scholar]
191. Hills CE, Younis MY, Bennett J, Siamantouras E, Liu KK, Squires PE. Calcium-sensing receptor activation increases cell-cell adhesion and beta-cell function. Cell Physiol Biochem. 2012;30:575–586. doi: 10.1159/000341439. [DOI] [PubMed] [Google Scholar]
192. Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nature genetics. 1995;11:389–394. doi: 10.1038/ng1295-389. [DOI] [PubMed] [Google Scholar]
193. Hobson SA, Wright J, Lee F, McNeil SE, Bilderback T, Rodland KD. Activation of the MAP kinase cascade by exogenous calcium-sensing receptor. Mol Cell Endocrinol. 2003;200:189–198. doi: 10.1016/s0303-7207(01)00749-3. [DOI] [PubMed] [Google Scholar]
194. Hodgkin MN, Hills CE, Squires PE. The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on. J Endocrinol. 2008;199:1–4. doi: 10.1677/JOE-08-0261. [DOI] [PubMed] [Google Scholar]
195. Hough TA, Bogani D, Cheeseman MT, Favor J, Nesbit MA, Thakker RV, Lyon MF. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci USA. 2004a;101:13566–13571. doi: 10.1073/pnas.0405516101. [DOI] [PMC free article] [PubMed] [Google Scholar]
196. Hough TA, Bogani D, Cheeseman MT, Favor J, Nesbit MA, Thakker RV, Lyon MF. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci USA. 2004b;101:13566–13571. doi: 10.1073/pnas.0405516101. [DOI] [PMC free article] [PubMed] [Google Scholar]
197. House MG, Kohlmeier L, Chattopadhyay N, Kifor O, Yamaguchi T, Leboff MS, Glowacki J, Brown EM. Expression of an extracellular calcium-sensing receptor in human and mouse bone marrow cells. J Bone Miner Res. 1997;12:1959–1970. doi: 10.1359/jbmr.1997.12.12.1959. [DOI] [PubMed] [Google Scholar]
198. Hovden S, Rejnmark L, Ladefoged SA, Nissen PH. AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia. Eur J Endocrinol. 2017;176:177–185. doi: 10.1530/EJE-16-0842. [DOI] [PubMed] [Google Scholar]
199. Howles SA, Hannan FM, Babinsky VN, Rogers A, Gorvin CM, Rust N, Nesbit MA, Thakker RV, Richardson T, McKenna MJ. Cinacalcet for symptomatic hypercalcemia caused by AP2S1 mutations. New Engl J Med. 2016;374:1396–1398. doi: 10.1056/NEJMc1511646. [DOI] [PMC free article] [PubMed] [Google Scholar]
200. Howles SA, Hannan FM, Gorvin CM, Piret SE, Paudyal A, Stewart M, Hough TA, Nesbit MA, Wells S, Brown SD, Cox RD, Thakker RV. Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation. JCI Insight. 2017;2 doi: 10.1172/jci.insight.96540. pii:96540. [DOI] [PMC free article] [PubMed] [Google Scholar]
201. Hu J, Jiang J, Costanzi S, Thomas C, Yang W, Feyen JH, Jacobson KA, Spiegel AM. A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator. J Biol Chem. 2006;281:21558–21565. doi: 10.1074/jbc.M603682200. [DOI] [PubMed] [Google Scholar]
202. Huang C, Miller RT. Novel Ca receptor signaling pathways for control of renal ion transport. Curr Opin Nephrol Hypertens. 2010;19:106–112. doi: 10.1097/MNH.0b013e328332e7b2. [DOI] [PubMed] [Google Scholar]
203. Huang CF, Handlogten ME, Miller RT. Parallel activation of phosphatidylinositol 4- kinase and phospholipase C by the extracellular calcium-sensing receptor. J Biol Chem. 2002;277:20293–20300. doi: 10.1074/jbc.M200831200. [DOI] [PubMed] [Google Scholar]
204. Huang CF, Hujer KM, Wu ZZ, Miller RT. The Ca2+-sensing receptor couples to Gα12/13 to activate phospholipase D in Madin-Darby canine kidney cells. Am J Physiol. 2004;286:C22–C30. doi: 10.1152/ajpcell.00229.2003. [DOI] [PubMed] [Google Scholar]
205. Huang Y, Breitwieser GE. Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem. 2007;282:9517–9525. doi: 10.1074/jbc.M609045200. [DOI] [PubMed] [Google Scholar]
206. Huang Y, Zhou Y, Castiblanco A, Yang W, Brown EM, Yang JJ. Multiple Ca(2+)- binding sites in the extracellular domain of the Ca(2+)-sensing receptor corresponding to cooperative Ca(2+) response. Biochemistry. 2009;48:388–398. doi: 10.1021/bi8014604. [DOI] [PMC free article] [PubMed] [Google Scholar]
207. Huang Y, Zhou Y, Yang W, Butters R, Lee HW, Li S, Castiblanco A, Brown EM, Yang JJ. Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem. 2007;282:19000–19010. doi: 10.1074/jbc.M701096200. [DOI] [PMC free article] [PubMed] [Google Scholar]
208. Hurtel-Lemaire AS, Mentaverri R, Caudrillier A, Cournarie F, Wattel A, Kamel S, Terwilliger EF, Brown EM, Brazier M. The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways. J Biol Chem. 2009;284:575–584. doi: 10.1074/jbc.M801668200. [DOI] [PubMed] [Google Scholar]
209. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, et al. alpha-Klotho as a regulator of calcium homeostasis. Science. 2007;316:1615–1618. doi: 10.1126/science.1135901. [DOI] [PubMed] [Google Scholar]
210. Jacobsen SE, Gether U, Bräuner-Osborne H. Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer. Sci Rep. 2017;7 doi: 10.1038/srep46355. 46355. [DOI] [PMC free article] [PubMed] [Google Scholar]
211. Janicic N, Soliman E, Pausova Z, Seldin MF, Riviere M, Szpirer J, Szpirer C, Hendy GN. Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16. Mamm Genome. 1995;6:798–801. doi: 10.1007/BF00539007. [DOI] [PubMed] [Google Scholar]
212. Jensen AA, Greenwood JR, Bräuner-Osborne H. The dance of the clams: twists and turns in the family C GPCR homodimer. Trends Pharmacol Sci. 2002;23:491–493. doi: 10.1016/s0165-6147(02)02107-7. [DOI] [PubMed] [Google Scholar]
213. John MR, Harfst E, Loeffler J, Belleli R, Mason J, Bruin GJ, Seuwen K, Klickstein LB, Mindeholm L, Widler L, Kneissel M. AXT914 a novel, orally-active parathyroid hormone- releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014;64:204–210. doi: 10.1016/j.bone.2014.04.015. [DOI] [PubMed] [Google Scholar]
214. Jones BL, Smith SM. Calcium-sensing receptor: A key target for extracellular calcium signaling in neurons. Front Physiol. 2016;7:116. doi: 10.3389/fphys.2016.00116. [DOI] [PMC free article] [PubMed] [Google Scholar]
215. Josephs TM, Keller AN, Khajehali E, DeBono A, Langmead CJ, Conigrave AD, Capuano B, Kufareva I, Gregory KJ, Leach K. Negative allosteric modulators of the human calcium sensing receptor bind to topographically distinct sites within the 7 transmembrane domain. Br J Pharmacol. 2019 doi: 10.1111/bph.14961. In Press. [DOI] [PMC free article] [PubMed] [Google Scholar]
216. Jungman E, Pirot F, Maibach H. Ex vivo calcium percutaneous eggression in normal and tape-stripped human skin. Cutan Ocul Toxicol. 2012;31:1–6. doi: 10.3109/15569527.2011.590570. [DOI] [PubMed] [Google Scholar]
217. Kallay E, Bonner E, Wrba F, Thakker RV, Peterlik M, Cross HS. Molecular and functional characterization of the extracellular calcium-sensing receptor in human colon cancer cells. Oncol Res. 2003;13:551–559. doi: 10.3727/000000003108748072. [DOI] [PubMed] [Google Scholar]
218. Kallay E, Kifor O, Chattopadhyay N, Brown EM, Bischof MG, Peterlik M, Cross HS. Calcium-dependent c-myc proto-oncogene expression and proliferation of Caco-2 cells: a role for a luminal extracellular calcium-sensing receptor. Biochem Biophys Res Commun. 1997;232:80–83. doi: 10.1006/bbrc.1997.6225. [DOI] [PubMed] [Google Scholar]
219. Kameda T, Mano H, Yamada Y, Takai H, Amizuka N, Kobori M, Izumi N, Kawashima H, Ozawa H, Ikeda K, Kameda A, Hakeda Y, Kumegawa M. Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun. 1998;245:419–422. doi: 10.1006/bbrc.1998.8448. [DOI] [PubMed] [Google Scholar]
220. Kanatani M, Sugimoto T, Kanzawa M, Yano S, Chihara K. High extracellular calcium inhibits osteoclast-like cell formation by directly acting on the calcium-sensing receptor existing in osteoclast precursor cells. Biochem Biophys Res Commun. 1999;261:144–148. doi: 10.1006/bbrc.1999.0932. [DOI] [PubMed] [Google Scholar]
221. Kantham L, Quinn S, Egbuna O, Baxi K, Butters R, Pang J, Pollak M, Goltzman D, Brown E. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am J Physiol Endocrinol Metab. 2009;297:E915–E923. doi: 10.1152/ajpendo.00315.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
222. Kapoor A, Satishchandra P, Ratnapriya R, Reddy R, Kadandale J, Shankar SK, Anand A. An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol. 2008;64:158–167. doi: 10.1002/ana.21428. [DOI] [PubMed] [Google Scholar]
223. Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol. 2013;53:531–556. doi: 10.1146/annurev-pharmtox-032112-135923. [DOI] [PMC free article] [PubMed] [Google Scholar]
224. Kawata T, Nagano N, Obi M, Miyata S, Koyama C, Kobayashi N, Wakita S, Wada M. Cinacalcet suppresses calcification of the aorta and heart in uremic rats. Kidney Int. 2008;74:1270–1277. doi: 10.1038/ki.2008.407. [DOI] [PubMed] [Google Scholar]
225. Kawata T, Tokunaga S, Murai M, Masuda N, Haruyama W, Shoukei Y, Hisada Y, Yanagida T, Miyazaki H, Wada M, Akizawa T, Fukagawa M. A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. PLoS One. 2018;13:e0195316. doi: 10.1371/journal.pone.0195316. [DOI] [PMC free article] [PubMed] [Google Scholar]
226. Keller AN, Kufareva I, Josephs TM, Diao J, Mai VT, Conigrave AD, Christopoulos A, Gregory KJ, Leach K. Identification of global and ligand-specific calcium sensing receptor activation mechanisms. Mol Pharmacol. 2018;93:619–630. doi: 10.1124/mol.118.112086. [DOI] [PMC free article] [PubMed] [Google Scholar]
227. Kelly BT, McCoy AJ, Spate K, Miller SE, Evans PR, Honing S, Owen DJ. A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex. Nature. 2008;456:976–979. doi: 10.1038/nature07422. [DOI] [PMC free article] [PubMed] [Google Scholar]
228. Kelly JC, Lungchukiet P, Macleod RJ. Extracellular calcium-sensing receptor inhibition of intestinal epithelial TNF signaling requires CaSR-mediated Wnt5a/Ror2 interaction. Front Physiol. 2011;2:17. doi: 10.3389/fphys.2011.00017. [DOI] [PMC free article] [PubMed] [Google Scholar]
229. Kenakin T, Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov. 2013;12:205–216. doi: 10.1038/nrd3954. [DOI] [PubMed] [Google Scholar]
230. Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL. A threshold for low-protein-diet-induced elevations in parathyroid hormone. Am J Clin Nutr. 2000;72:168–173. doi: 10.1093/ajcn/72.1.168. [DOI] [PubMed] [Google Scholar]
231. Kessler A, Faure H, Petrel C, Rognan D, Cesario M, Ruat M, Dauban P, Dodd RH. N1- Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4- chlorophenylcarboxamide (calhex 231) as a new calcium sensing receptor ligand demonstrating potent calcilytic activity. J Med Chem. 2006;49:5119–5128. doi: 10.1021/jm051233+. [DOI] [PubMed] [Google Scholar]
232. Kessler A, Faure H, Roussanne MC, Ferry S, Ruat M, Dauban P, Dodd RH. N(1)- Arylsulfonyl-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexanes: a new class of calcilytic agents acting at the calcium-sensing receptor. Chembiochem. 2004;5:1131–1136. doi: 10.1002/cbic.200400049. [DOI] [PubMed] [Google Scholar]
233. Kifor O, Diaz R, Butters R, Brown EM. The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells. J Bone Miner Res. 1997;12:715–725. doi: 10.1359/jbmr.1997.12.5.715. [DOI] [PubMed] [Google Scholar]
234. Kifor O, Diaz R, Butters R, Kifor I, Brown EM. The calcium-sensing receptor is localized in caveolin-rich plasma membrane domains of bovine parathyroid cells. J Biol Chem. 1998;273:21708–21713. doi: 10.1074/jbc.273.34.21708. [DOI] [PubMed] [Google Scholar]
235. Kifor O, Kifor I, Moore F, Butters R, Cantor T, Gao P, Brown E. Decreased expression of caveolin-1 and altered regulation of mitogen-activated protein kinase in cultured bovine parathyroid cells and human parathyroid adenomas. J Clin Endocrinol Metab. 2003;88:4455–4464. doi: 10.1210/jc.2002-021427. [DOI] [PubMed] [Google Scholar]
236. Kifor O, MacLeod RJ, Diaz R, Bai M, Yamaguchi T, Yao T, I K, Brown EM. Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. Am J Physio. 2001;280:F291–F302. doi: 10.1152/ajprenal.2001.280.2.F291. [DOI] [PubMed] [Google Scholar]
237. Kifor O, Moore FD, Wang P, Goldstein M, Vassilev P, Kifor I, Hebert SC, Brown EM. Reduced immunostaining for the extracellular Ca2+ sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab. 1996;81:1598–1606. doi: 10.1210/jcem.81.4.8636374. [DOI] [PubMed] [Google Scholar]
238. Kim CH, Braud S, Isaac JT, Roche KW. Protein kinase C phosphorylation of the metabotropic glutamate receptor mGluR5 on Serine 839 regulates Ca2+ oscillations. J Biol Chem. 2005;280:25409–25415. doi: 10.1074/jbc.M502644200. [DOI] [PubMed] [Google Scholar]
239. Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W. Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection. Ann Clin Transl Neurol. 2014;1:851–866. doi: 10.1002/acn3.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
240. Kim JY, Kim N, Yenari MA, Chang W. Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular calcium-sensing receptor protect neurons against traumatic brain injury. J Neurotrauma. 2013;30:1170–1176. doi: 10.1089/neu.2012.2691. [DOI] [PMC free article] [PubMed] [Google Scholar]
241. Kim W, Takyar FM, Swan K, Jeong J, VanHouten J, Sullivan C, Dann P, Yu H, Fiaschi-Taesch N, Chang W, Wysolmerski J. Calcium-sensing receptor promotes breast cancer by stimulating intracrine actions of parathyroid hormone-related protein. Cancer Res. 2016;76:5348–5360. doi: 10.1158/0008-5472.CAN-15-2614. [DOI] [PMC free article] [PubMed] [Google Scholar]
242. Kim W, Wysolmerski JJ. Calcium-sensing receptor in breast physiology and cancer. Front Physiol. 2016;7:440. doi: 10.3389/fphys.2016.00440. [DOI] [PMC free article] [PubMed] [Google Scholar]
243. Kirberger M, Wang X, Deng H, Yang W, Chen G, Yang JJ. Statistical analysis of structural characteristics of protein Ca2+-binding sites. J Biol Inorg Chem. 2008;13:1169–1181. doi: 10.1007/s00775-008-0402-7. [DOI] [PubMed] [Google Scholar]
244. Kitay AM, Schneebacher MT, Schmitt A, Heschl K, Kopic S, Alfadda T, Alsaihati A, Link A, Geibel JP. Modulations in extracellular calcium lead to H(+)-ATPase-dependent acid secretion: a clarification of PPI failure. Am J Physiol-Gastr L. 2018;315:G36–G42. doi: 10.1152/ajpgi.00132.2017. [DOI] [PubMed] [Google Scholar]
245. Kitsou-Mylona I, Burns CJ, Squires PE, Persaud SJ, Jones PM. A role for the extracellular calcium-sensing receptor in cell-cell communication in pancreatic islets of langerhans. Cell Physiol Biochem. 2008;22:557–566. doi: 10.1159/000185540. [DOI] [PubMed] [Google Scholar]
246. Koehl A, Hu H, Feng D, Sun B, Zhang Y, Robertson MJ, Chu M, Kobilka TS, Laermans T, Steyaert J, Tarrasch J, Dutta S, Fonseca R, Weis WI, Mathiesen JM, Skiniotis G, Kobilka BK. Structural insights into the activation of metabotropic glutamate receptors. Nature. 2019;566:79–84. doi: 10.1038/s41586-019-0881-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
247. Koh J, Dar M, Untch BR, Dixit D, Shi Y, Yang Z, Adam MA, Dressman H, Wang X, Gesty-Palmer D, Marks JR, Spurney R, Druey KM, Olson JA., Jr Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium- sensing receptor. Mol Endocrinol. 2011;25:867–876. doi: 10.1210/me.2010-0277. [DOI] [PMC free article] [PubMed] [Google Scholar]
248. Komuves L, Oda Y, Tu CL, Chang WH, Ho-Pao CL, Mauro T, Bikle DD. Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation. J Cell Physiol. 2002;192:45–54. doi: 10.1002/jcp.10107. [DOI] [PubMed] [Google Scholar]
249. Kos CH, Karaplis AC, Peng JB, Hediger MA, Goltzman D, Mohammad KS, Guise TA, Pollak MR. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest. 2003;111:1021–1028. doi: 10.1172/JCI17416. [DOI] [PMC free article] [PubMed] [Google Scholar]
250. Krissinel E, Henrick K. Inference of macromolecular assemblies from crystalline state. J Mol Biol. 2007;372:774–797. doi: 10.1016/j.jmb.2007.05.022. [DOI] [PubMed] [Google Scholar]
251. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 2013;504:101–106. doi: 10.1038/nature12735. [DOI] [PMC free article] [PubMed] [Google Scholar]
252. Kumar S, Matheny CJ, Hoffman SJ, Marquis RW, Schultz M, Liang X, Vasko JA, Stroup GB, Vaden VR, Haley H, Fox J, DelMar EG, Nemeth EF, Lago AM, Callahan JF, Bhatnagar P, Huffman WF, Gowen M, Yi B, Danoff TM, Fitzpatrick LA. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone. 2010;46:534–542. doi: 10.1016/j.bone.2009.09.028. [DOI] [PubMed] [Google Scholar]
253. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S, Jingami H, Morikawa K. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature. 2000;407:971–977. doi: 10.1038/35039564. [DOI] [PubMed] [Google Scholar]
254. Kurosawa M, Shimizu Y, Tsukagoshi H, Ueki M. Elevated levels of peripheral-blood, naturally occurring aliphatic polyamines in bronchial asthmatic patients with active symptoms. Allergy. 1992;47:638–643. doi: 10.1111/j.1398-9995.1992.tb02388.x. [DOI] [PubMed] [Google Scholar]
255. Ladds G, Goddard A, Hill C, Thornton S, Davey J. Differential effects of RGS proteins on G alpha(q) and G alpha(11) activity. Cell Signal. 2007;19:103–113. doi: 10.1016/j.cellsig.2006.05.027. [DOI] [PubMed] [Google Scholar]
256. Lagerström MC, Schiöth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008;7:339–357. doi: 10.1038/nrd2518. [DOI] [PubMed] [Google Scholar]
257. Lazarus S, Pretorius CJ, Khafagi F, Campion KL, Brennan SC, Conigrave AD, Brown EM, Ward DT. A novel mutation of the primary protein kinase C phosphorylation site in the calcium-sensing receptor causes autosomal dominant hypocalcemia. Eur J Endocrinol. 2011;164:429–435. doi: 10.1530/EJE-10-0907. [DOI] [PubMed] [Google Scholar]
258. Leach K, Gregory KJ. Molecular insights into allosteric modulation of Class C G protein- coupled receptors. Pharmacol Res. 2017;116:105–118. doi: 10.1016/j.phrs.2016.12.006. [DOI] [PubMed] [Google Scholar]
259. Leach K, Gregory KJ, Kufareva I, Khajehali E, Cook AE, Abagyan R, Conigrave AD, Sexton PM, Christopoulos A. Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor. Cell Res. 2016;26:574–592. doi: 10.1038/cr.2016.36. [DOI] [PMC free article] [PubMed] [Google Scholar]
260. Leach K, Sexton PM, Christopoulos A. Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol Sci. 2007;28:382–389. doi: 10.1016/j.tips.2007.06.004. [DOI] [PubMed] [Google Scholar]
261. Leach K, Sexton PM, Christopoulos A, Conigrave AD. Engendering biased signalling from the calcium-sensing receptor for the pharmacotherapy of diverse disorders. Br J Pharmacol. 2014;171:1142–1155. doi: 10.1111/bph.12420. [DOI] [PMC free article] [PubMed] [Google Scholar]
262. Leach K, Wen A, Cook AE, Sexton PM, Conigrave AD, Christopoulos A. Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium- sensing receptor by positive and negative allosteric modulators. Endocrinology. 2013;154:1105–1116. doi: 10.1210/en.2012-1887. [DOI] [PubMed] [Google Scholar]
263. Leach K, Wen A, Davey AE, Sexton PM, Conigrave AD, Christopoulos A. Identification of molecular phenotypes and biased signaling induced by naturally occurring mutations of the human calcium-sensing receptor. Endocrinology. 2012;153:4304–4316. doi: 10.1210/en.2012-1449. [DOI] [PubMed] [Google Scholar]
264. LeBoff MS, Shoback D, Brown EM, Thatcher J, Leombruno R, Beaudoin D, Henry M, Wilson R, Pallotta J, Marynick S, Stock J, Leight G. Regulation of parathyroid hormone release and cytosolic calcium by extracellular calcium in dispersed and cultured bovine and pathological human parathyroid cells. J Clin Invest. 1985;75:49–57. doi: 10.1172/JCI111696. [DOI] [PMC free article] [PubMed] [Google Scholar]
265. Lee H, Mun H-C, Lewis NC, Crouch MF, Culverston EL, Mason RS, Conigrave AD. Allosteric activation of the extracellular Ca2+-sensing receptor by L-amino acids enhances ERK1/2 phosphorylation. Biochem J. 2007;404:141–149. doi: 10.1042/BJ20061826. [DOI] [PMC free article] [PubMed] [Google Scholar]
266. Lee JJ, Liu X, O'Neill D, Beggs MR, Weissgerber P, Flockerzi V, Chen XZ, Dimke H, Alexander RT. Activation of the calcium sensing receptor attenuates TRPV6- dependent intestinal calcium absorption. JCI Insight. 2019;4:e128013. doi: 10.1172/jci.insight.128013. [DOI] [PMC free article] [PubMed] [Google Scholar]
267. Letz S, Haag C, Schulze E, Frank-Raue K, Raue F, Hofner B, Mayr B, Schofl C. Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome Type 5 and autosomal dominant hypocalcemia. PLoS One. 2014;9:e115178. doi: 10.1371/journal.pone.0115178. [DOI] [PMC free article] [PubMed] [Google Scholar]
268. Letz S, Rus R, Haag C, Dorr HG, Schnabel D, Mohlig M, Schulze E, Frank-Raue K, Raue F, Mayr B, Schofl C. Novel activating mutations of the calcium-sensing receptor: the calcilytic NPS-2143 mitigates excessive signal transduction of mutant receptors. J Clin Endocrinol Metab. 2010;95:E229–233. doi: 10.1210/jc.2010-0651. [DOI] [PubMed] [Google Scholar]
269. Li D, Opas EE, Tuluc F, Metzger DL, Hou C, Hakonarson H, Levine MA. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J Clin Endocrinol Metab. 2014a;99:E1774–1783. doi: 10.1210/jc.2014-1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
270. Li X, Kong X, Jiang L, Ma T, Yan S, Yuan C, Yang Q. A genetic polymorphism (rs17251221) in the calcium-sensing receptor is associated with breast cancer susceptibility and prognosis. Cell Physiol Biochem. 2014b;33:165–172. doi: 10.1159/000356659. [DOI] [PubMed] [Google Scholar]
271. Lietman SA, Tenenbaum-Rakover Y, Jap TS, Yi-Chi W, De-Ming Y, Ding C, Kussiny N, Levine MA. A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. J Clin Endocrinol Metab. 2009;94:4372–4379. doi: 10.1210/jc.2008-2484. [DOI] [PMC free article] [PubMed] [Google Scholar]
272. Liou AP, Sei Y, Zhao X, Feng J, Lu X, Thomas C, Pechhold S, Raybould HE, Wank SA. The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. Am J Physiol-Gastr L. 2011;300:G538–546. doi: 10.1152/ajpgi.00342.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
273. Liu G, Cao W, Jia G, Zhao H, Chen X, Wang J. Calcium-sensing receptor in nutrient sensing: an insight into the modulation of intestinal homoeostasis. Br J Nutr. 2018;120:881–890. doi: 10.1017/S0007114518002088. [DOI] [PubMed] [Google Scholar]
274. Liu G, Hu X, Chakrabarty S. Calcium sensing receptor down-regulates malignant cell behavior and promotes chemosensitivity in human breast cancer cells. Cell Calcium. 2009;45:216–225. doi: 10.1016/j.ceca.2008.10.004. [DOI] [PubMed] [Google Scholar]
275. Liu XL, Lu YS, Gao JY, Marshall C, Xiao M, Miao DS, Karaplis A, Goltzman D, Ding J. Calcium sensing receptor absence delays postnatal brain development via direct and indirect mechanisms. Mol Neurobiol. 2013;48:590–600. doi: 10.1007/s12035-013-8448-0. [DOI] [PubMed] [Google Scholar]
276. Locatelli F, Cannata-Andia JB, Drueke TB, Horl WH, Fouque D, Heimburger O, Ritz E. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant. 2002;17:723–731. doi: 10.1093/ndt/17.5.723. [DOI] [PubMed] [Google Scholar]
277. Lorenz S, Frenzel R, Paschke R, Breitwieser GE, Miedlich SU. Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: Role of G protein-coupled receptor kinases, protein kinase C and β-arrestins. Endocrinology. 2007;148:2398–2404. doi: 10.1210/en.2006-1035. [DOI] [PubMed] [Google Scholar]
278. Loupy A, Ramakrishnan S, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen E, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd R, Ruat M, Houillier P. PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor. J Clin Invest. 2012;122:3355–3367. doi: 10.1172/JCI57407. [DOI] [PMC free article] [PubMed] [Google Scholar]
279. Lozano-Ortega G, Waser N, Bensink ME, Goring S, Bennett H, Block GA, Chertow GM, Trotman ML, Cooper K, Levy AR, Belozeroff V. Effects of calcimimetics on long-term outcomes in dialysis patients: literature review and Bayesian meta-analysis. J Comp Eff Res. 2018;7:693–707. doi: 10.2217/cer-2018-0015. [DOI] [PubMed] [Google Scholar]
280. Lu JY, Yang Y, Gnacadja G, Christopoulos A, Reagan JD. Effect of the calcimimetic R- 568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on correcting inactivating mutations in the human calcium-sensing receptor. J Pharmacol Exp Ther. 2009;331:775–786. doi: 10.1124/jpet.109.159228. [DOI] [PubMed] [Google Scholar]
281. Ma JN, Owens M, Gustafsson M, Jensen J, Tabatabaei A, Schmelzer K, Olsson R, Burstein ES. Characterization of highly efficacious allosteric agonists of the human calcium- sensing receptor. J Pharmacol Exp Ther. 2011;337:275–284. doi: 10.1124/jpet.110.178194. [DOI] [PubMed] [Google Scholar]
282. MacLeod RJ, Chattopadhyay N, Brown EM. PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation. Am J Physiol. 2003;284:E435–E442. doi: 10.1152/ajpendo.00143.2002. [DOI] [PubMed] [Google Scholar]
283. MacLeod RJ, Yano S, Chattopadhyay N, Brown EM. Extracellular calcium-sensing receptor transactivates the epidermal growth factor receptor by a triple-membrane-spanning signaling mechanism. Biochem Biophys Res Comm. 2004;320:455–460. doi: 10.1016/j.bbrc.2004.05.198. [DOI] [PubMed] [Google Scholar]
284. Makita N, Ando T, Sato J, Manaka K, Mitani K, Kikuchi Y, Niwa T, Ootaki M, Takeba Y, Matsumoto N, Kawakami A, Ogawa T, Nangaku M, Iiri T. Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody. JCI Insight. 2019;4 doi: 10.1172/jci.insight.126449. [DOI] [PMC free article] [PubMed] [Google Scholar]
285. Makita N, Iiri T. Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia. Endocr J. 2014;61:303–309. doi: 10.1507/endocrj.ej13-0453. [DOI] [PubMed] [Google Scholar]
286. Makita N, Sato J, Manaka K, Shoji Y, Oishi A, Hashimoto M, Fujita T, Iiri T. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci USA. 2007;104:5443–5448. doi: 10.1073/pnas.0701290104. [DOI] [PMC free article] [PubMed] [Google Scholar]
287. Mamillapalli R, VanHouten J, Zawalich W, Wysolmerski J. Switching of G-protein usage by the calcium-sensing receptor reverses its effect on parathyroid hormone-related protein secretion in normal versus malignant breast cells. J Biol Chem. 2008;283:24435–24447. doi: 10.1074/jbc.M801738200. [DOI] [PMC free article] [PubMed] [Google Scholar]
288. Mamillapalli R, Wysolmerski J. The calcium-sensing receptor couples to Gαs and regulates PTHrP and ACTH secretion in pituitary cells. J Endocrinol. 2010;204:287–297. doi: 10.1677/JOE-09-0183. [DOI] [PMC free article] [PubMed] [Google Scholar]
289. Mannstadt M, Harris M, Bravenboer B, Chitturi S, Dreijerink KM, Lambright DG, Lim ET, Daly MJ, Gabriel S, Juppner H. Germline mutations affecting Gα11 in hypoparathyroidism. N Engl J Med. 2013;368:2532–2534. doi: 10.1056/NEJMc1300278. [DOI] [PMC free article] [PubMed] [Google Scholar]
290. Margolis KG, Stevanovic K, Karamooz N, Li ZS, Ahuja A, D’Autreaux F, Saurman V, Chalazonitis A, Gershon MD. Enteric neuronal density contributes to the severity of intestinal inflammation. Gastroenterology. 2011;141:588–598. doi: 10.1053/j.gastro.2011.04.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
291. Marie PJ. The calcium-sensing receptor in bone cells: a potential therapeutic target in osteoporosis. Bone. 2010;46:571–576. doi: 10.1016/j.bone.2009.07.082. [DOI] [PubMed] [Google Scholar]
292. Masvidal L, Iniesta R, Casala C, Galvan P, Rodriguez E, Lavarino C, Mora J, de Torres C. Polymorphisms in the calcium-sensing receptor gene are associated with clinical outcome of neuroblastoma. PLoS One. 2013;8:e59762. doi: 10.1371/journal.pone.0059762. [DOI] [PMC free article] [PubMed] [Google Scholar]
293. Masvidal L, Iniesta R, Garcia M, Casala C, Lavarino C, Mora J, de Torres C. Genetic variants in the promoter region of the calcium-sensing receptor gene are associated with its down-regulation in neuroblastic tumors. Mol Carcinog. 2017;56:1281–1289. doi: 10.1002/mc.22589. [DOI] [PubMed] [Google Scholar]
294. McCormick WD, Atkinson-Dell R, Campion KL, Mun HC, Conigrave AD, Ward DT. Increased receptor stimulation elicits differential calcium-sensing receptor (T888) dephosphorylation. J Biol Chem. 2010;285:14170–14177. doi: 10.1074/jbc.M109.071084. [DOI] [PMC free article] [PubMed] [Google Scholar]
295. McGehee DS, Aldersberg M, Liu KP, Hsuing S, Heath MJ, Tamir H. Mechanism of extracellular Ca2+ receptor-stimulated hormone release from sheep thyroid parafollicular cells. J Physiol (Lond) 1997;502:31–44. doi: 10.1111/j.1469-7793.1997.031bl.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
296. McLarnon S, Holden D, Ward D, Jones M, Elliott A, Riccardi D. Aminoglycoside antibiotics induce pH-sensitive activation of the calcium-sensing receptor. Biochem Biophys Res Commun. 2002;297:71–77. doi: 10.1016/s0006-291x(02)02133-2. [DOI] [PubMed] [Google Scholar]
297. McLarnon SJ, Riccardi D. Physiological and pharmacological agonists of the extracellular Ca2+-sensing receptor. Eur J Pharmacol. 2002;447:271–278. doi: 10.1016/s0014-2999(02)01849-6. [DOI] [PubMed] [Google Scholar]
298. McMurtry CT, Schranck FW, Walkenhorst DA, Murphy WA, Kocher DB, Teitelbaum SL, Rupich RC, Whyte MP. Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am J Med. 1992;93:247–258. doi: 10.1016/0002-9343(92)90229-5. [DOI] [PubMed] [Google Scholar]
299. Meng K, Xu J, Zhang C, Zhang R, Yang H, Liao C, Jiao J. Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3/6 channels in cultured human mesangial cells. PLoS One. 2014;9:e98777. doi: 10.1371/journal.pone.0098777. [DOI] [PMC free article] [PubMed] [Google Scholar]
300. Menon GK, Elias PM. Ultrastructural localization of calcium in psoriatic and normal human epidermis. Arch Dermatol. 1991;127:57–63. [PubMed] [Google Scholar]
301. Menon GK, Elias PM, Feingold KR. Integrity of the permeability barrier is crucial for maintenance of the epidermal calcium gradient. Br J Dermatol. 1994;130:139–147. doi: 10.1111/j.1365-2133.1994.tb02892.x. [DOI] [PubMed] [Google Scholar]
302. Menon GK, Grayson S, Elias PM. Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ion-capture cytochemistry. J Invest Dermatol. 1985;84:508–512. doi: 10.1111/1523-1747.ep12273485. [DOI] [PubMed] [Google Scholar]
303. Mentaverri R, Yano S, Chattopadhyay N, Petit L, Kifor O, Kamel S, Terwilliger EF, Brazier M, Brown EM. The calcium sensing receptor is directly involved in both osteoclast differentiation and apoptosis. FASEB J. 2006;20:2562–2564. doi: 10.1096/fj.06-6304fje. [DOI] [PubMed] [Google Scholar]
304. Miedlich SU, Gama L, Seuwen K, Wolf RM, Breitwieser GE. Homology modeling of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site. J Biol Chem. 2004;279:7254–7263. doi: 10.1074/jbc.M307191200. [DOI] [PubMed] [Google Scholar]
305. Miller RT. Control of renal calcium, phosphate, electrolyte, and water excretion by the calcium-sensing receptor. Best Pract Res Clin Endocrinol Metab. 2013;27:345–358. doi: 10.1016/j.beem.2013.04.009. [DOI] [PubMed] [Google Scholar]
306. Miller-Fleming L, Olin-Sandoval V, Campbell K, Ralser M. Remaining mysteries of molecular biology: The role of polyamines in the cell. J Mol Biol. 2015;427:3389–3406. doi: 10.1016/j.jmb.2015.06.020. [DOI] [PubMed] [Google Scholar]
307. Mine Y, Zhang H. Anti-inflammatory effects of poly-L-lysine in intestinal mucosal system mediated by calcium-sensing receptor activation. J Agric Food Chem. 2015;63:10437–10447. doi: 10.1021/acs.jafc.5b03812. [DOI] [PubMed] [Google Scholar]
308. Mizobuchi M, Ritter CS, Krits I, Slatopolsky E, Sicard G, Brown AJ. Calcium-sensing receptor expression is regulated by glial cells missing-2 in human parathyroid cells. J Bone Miner Res. 2009;24:1173–1179. doi: 10.1359/JBMR.090211. [DOI] [PMC free article] [PubMed] [Google Scholar]
309. Mos I, Jacobsen SE, Foster SR, Brauner-Osborne H. Calcium-Sensing Receptor Internalization Is beta-Arrestin-Dependent and Modulated by Allosteric Ligands. Mol Pharmacol. 2019a;96:463–474. doi: 10.1124/mol.119.116772. [DOI] [PubMed] [Google Scholar]
310. Mos I, Jacobsen SE, Foster SR, Brauner-Osborne H. Calcium-sensing receptor internalization is β-arrestin-dependent and modulated by allosteric ligands. Mol Pharmacol. 2019b;96:463–474. doi: 10.1124/mol.119.116772. [DOI] [PubMed] [Google Scholar]
311. Muff R, Nemeth EF, Haller-Brem S, Fischer JA. Regulation of hormone secretion and cytosolic Ca2+ by extracellular Ca2+ in parathyroid cells and C-cells: role of voltage- sensitive Ca2+ channels. Arch Biochem Biophys. 1988;265:128–135. doi: 10.1016/0003-9861(88)90378-5. [DOI] [PubMed] [Google Scholar]
312. Mun HC, Culverston EL, Franks AH, Collyer CA, Clifton-Bligh RJ, Conigrave AD. A double mutation in the extracellular Ca2+-sensing receptor’s venus flytrap domain that selectively disables L-amino acid sensing. J Biol Chem. 2005;280:29067–29072. doi: 10.1074/jbc.M500002200. [DOI] [PubMed] [Google Scholar]
313. Mun HC, Franks AH, Culverston EL, Krapcho K, Nemeth EF, Conigrave AD. The Venus Fly Trap domain of the extracellular Ca2+ -sensing receptor is required for L-amino acid sensing. J Biol Chem. 2004;279:51739–51744. doi: 10.1074/jbc.M406164/200. [DOI] [PubMed] [Google Scholar]
314. Mun HC, Leach KM, Conigrave AD. L-amino acids promote calcitonin release via a calcium-sensing receptor: Gq/11-mediated pathway in human C-cells. Endocrinology. 2019;160:1590–1599. doi: 10.1210/en.2018-00860. [DOI] [PubMed] [Google Scholar]
315. Munk C, Isberg V, Mordalski S, Harpsoe K, Rataj K, Hauser AS, Kolb P, Bojarski AJ, Vriend G, Gloriam DE. GPCRdb: the G protein-coupled receptor database - an introduction. Br J Pharmacol. 2016;173:2195–2207. doi: 10.1111/bph.13509. [DOI] [PMC free article] [PubMed] [Google Scholar]
316. Murer H, Hernando N, Forster I, Biber J. Molecular aspects in the regulation of renal inorganic phosphate reabsorption: the type IIa sodium/inorganic phosphate co-transporter as the key player. Curr Opin Nephrol Hypertens. 2001;10:555–561. doi: 10.1097/00041552-200109000-00002. [DOI] [PubMed] [Google Scholar]
317. Muresan Z, MacGregor R. The release of parathyroid hormone and the exocytosis of a proteoglycan are modulated by extracellular Ca2+ in a similar manner. Mol Biol Cell. 1994;5:725–737. doi: 10.1091/mbc.5.7.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
318. Muto T, Tsuchiya D, Morikawa K, Jingami H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci USA. 2007;104:3759–3764. doi: 10.1073/pnas.0611577104. [DOI] [PMC free article] [PubMed] [Google Scholar]
319. Nakagawa K, Parekh N, Koleganova N, Ritz E, Schaefer F, Schmitt CP. Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats. Pediatr Nephrol. 2009;24:1385–1389. doi: 10.1007/s00467-009-1153-6. [DOI] [PubMed] [Google Scholar]
320. Nakamura H, Tsujiguchi H, Hara A, Kambayashi Y, Miyagi S, Thu Nguyen TT, Suzuki K, Tao Y, Sakamoto Y, Shimizu Y, Yamamoto N, et al. Dietary calcium intake and hypertension: importance of serum concentrations of 25-hydroxyvitamin D. Nutrients. 2019;11 doi: 10.3390/nu11040911. pii:E911. [DOI] [PMC free article] [PubMed] [Google Scholar]
321. Nearing J, Betka M, Quinn S, Hentschel H, Elger M, Baum M, Bai M, Chattopadyhay N, Brown EM, Hebert SC, Harris HW. Polyvalent cation receptor proteins (CaRs) are salinity sensors in fish. Proc Natl Acad Sci USA. 2002;99:9231–9236. doi: 10.1073/pnas.152294399. [DOI] [PMC free article] [PubMed] [Google Scholar]
322. Nemeth EF, Scarpa A. Cytosolic Ca2+ and the regulation of secretion in parathyroid cells. FEBS Lett. 1986;203:15–19. doi: 10.1016/0014-5793(86)81427-2. [DOI] [PubMed] [Google Scholar]
323. Nemeth EF, Scarpa A. Rapid mobilization of cellular Ca2+ in bovine parathyroid cells evoked by extracellular divalent cations. Evidence for a cell surface calcium receptor. J Biol Chem. 1987;262:5188–5196. [PubMed] [Google Scholar]
324. Nemeth EF, Van Wagenen BC, Balandrin MF. Discovery and development of calcimimetic and calcilytic compounds. Prog Med Chem. 2018;57:1–86. doi: 10.1016/bs.pmch.2017.12.001. [DOI] [PubMed] [Google Scholar]
325. Nemeth EF, Wallace J, Scarpa A. Stimulus-secretion coupling in bovine parathyroid cells. Dissociation between secretion and net changes in cytosolic Ca2+ . J Biol Chem. 1986;261:2668–2674. [PubMed] [Google Scholar]
326. Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med. 2013a;368:2476–2486. doi: 10.1056/NEJMoa1300253. [DOI] [PMC free article] [PubMed] [Google Scholar]
327. Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, Gregory L, Rimmer AJ, Rust N, Graham U, Morrison PJ, Hunter SJ, Whyte MP, McVean G, Buck D, Thakker RV. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet. 2013b;45:93–97. doi: 10.1038/ng.2492. [DOI] [PMC free article] [PubMed] [Google Scholar]
328. North ML, Grasemann H, Khanna N, Inman MD, Gauvreau GM, Scott JA. Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma. Am J Respir Cell Mol Biol. 2013;48:694–702. doi: 10.1165/rcmb.2012-0323OC. [DOI] [PubMed] [Google Scholar]
329. O'Hara PJ, Sheppard PO, Thogersen H, Venezia D, Haldeman BA, McGrane V, Houamed KM, Thomsen C, Gilbert TL, Mulvihill ER. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron. 1993;11:41–52. doi: 10.1016/0896-6273(93)90269-w. [DOI] [PubMed] [Google Scholar]
330. Oda Y, Hu L, Nguyen T, Fong C, Tu CL, Bikle DD. Combined deletion of the vitamin D receptor and calcium-sensing receptor delays wound re-epithelialization. Endocrinology. 2017;158:1929–1938. doi: 10.1210/en.2017-00061. [DOI] [PMC free article] [PubMed] [Google Scholar]
331. Oda Y, Tu CL, Pillai S, Bikle DD. The calcium sensing receptor and its alternatively spliced form in keratinocyte differentiation. J Biol Chem. 1998;273:23344–23352. doi: 10.1074/jbc.273.36.23344. [DOI] [PubMed] [Google Scholar]
332. Odenwald T, Nakagawa K, Hadtstein C, Roesch F, Gohlke P, Ritz E, Schaefer F, Schmitt CP. Acute blood pressure effects and chronic hypotensive action of calcimimetics in uremic rats. J Am Soc Nephrol. 2006;17:655–662. doi: 10.1681/ASN.2005090914. [DOI] [PubMed] [Google Scholar]
333. Ogata H, Ritz E, Odoni G, Amann K, Orth SR. Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. J Am Soc Nephrol. 2003;14:959–967. doi: 10.1097/01.asn.0000056188.23717.e5. [DOI] [PubMed] [Google Scholar]
334. Oh YS, Seo EH, Lee YS, Cho SC, Jung HS, Park SC, Jun HS. Increase of calcium sensing receptor expression is related to compensatory insulin secretion during aging in mice. PLoS One. 2016;11:e0159689. doi: 10.1371/journal.pone.0159689. [DOI] [PMC free article] [PubMed] [Google Scholar]
335. Ohsu T, Amino Y, Nagasaki H, Yamanaka T, Takeshita S, Hatanaka T, Maruyama Y, Miyamura N, Eto Y. Involvement of the calcium-sensing receptor in human taste perception. J Biol Chem. 2010;285:1016–1022. doi: 10.1074/jbc.M109.029165. [DOI] [PMC free article] [PubMed] [Google Scholar]
336. Owen JL, Cheng SX, Ge Y, Sahay B, Mohamadzadeh M. The role of the calcium-sensing receptor in gastrointestinal inflammation. Semin Cell Dev Biol. 2016;49:44–51. doi: 10.1016/j.semcdb.2015.10.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
337. Pais R, Gribble FM, Reimann F. Signalling pathways involved in the detection of peptones by murine small intestinal enteroendocrine L-cells. Peptides. 2016;77:9–15. doi: 10.1016/j.peptides.2015.07.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
338. Pallais JC, Kemp EH, Bergwitz C, Kantham L, Slovik DM, Weetman AP, Brown EM. Autoimmune hypocalciuric hypercalcemia unresponsive to glucocorticoid therapy in a patient with blocking autoantibodies against the calcium-sensing receptor. J Clin Endocrinol Metab. 2011;96:672–680. doi: 10.1210/jc.2010-1739. [DOI] [PMC free article] [PubMed] [Google Scholar]
339. Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP, Thakker RV. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest. 1995;96:2683–2692. doi: 10.1172/JCI118335. [DOI] [PMC free article] [PubMed] [Google Scholar]
340. Pearce SH, Williamson C, Kifor O, Bai M, Coulthard MG, Davies M, Lewis-Barned N, McCredie D, Powell H, Kendall-Taylor P, Brown EM, Thakker RV. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996;335:1115–1122. doi: 10.1056/NEJM199610103351505. [DOI] [PubMed] [Google Scholar]
341. Peiris D, Pacheco I, Spencer C, MacLeod RJ. The extracellular calcium-sensing receptor reciprocally regulates the secretion of BMP-2 and the BMP antagonist Noggin in colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2007;292:G753–766. doi: 10.1152/ajpgi.00225.2006. [DOI] [PubMed] [Google Scholar]
342. Perez-Benito L, Doornbos MLJ, Cordomi A, Peeters L, Lavreysen H, Pardo L, Tresadern G. Molecular switches of allosteric modulation of the metabotropic glutamate 2 receptor. Structure. 2017;25:1153–1162 e1154. doi: 10.1016/j.str.2017.05.021. [DOI] [PubMed] [Google Scholar]
343. Petrel C, Kessler A, Dauban P, Dodd RH, Rognan D, Ruat M. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J Biol Chem. 2004;279:18990–18997. doi: 10.1074/jbc.M400724200. [DOI] [PubMed] [Google Scholar]
344. Petrel C, Kessler A, Maslah F, Dauban P, Dodd RH, Rognan D, Ruat M. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor. J Biol Chem. 2003;278:49487–49494. doi: 10.1074/jbc.M308010200. [DOI] [PubMed] [Google Scholar]
345. Pi M, Faber P, Ekema G, Jackson PD, Ting A, Wang N, Fontilla-Poole M, Mays RW, Brunden KR, Harrington JJ, Quarles LD. Identification of a novel extracellular cation-sensing G-protein-coupled receptor. J Biol Chem. 2005a;280:40201–40209. doi: 10.1074/jbc.M505186200. [DOI] [PMC free article] [PubMed] [Google Scholar]
346. Pi M, Oakley RH, Gesty-Palmer D, Cruickshank RD, Spurney RF, Luttrell LM, Quarles LD. β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitization. Mol Endocrinol. 2005b;19:1078–1087. doi: 10.1210/me.2004-0450. [DOI] [PubMed] [Google Scholar]
347. Pi M, Spurney RF, Tu QS, Hinson T, Quarles LD. Calcium-sensing receptor activation of Rho involves filamin and Rho-guanine nucleotide exchange factor. Endocrinology. 2002;143:3830–3838. doi: 10.1210/en.2002-220240. [DOI] [PubMed] [Google Scholar]
348. Pidasheva S, Grant M, Canaff L, Ercan O, Kumar U, Hendy GN. Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly. Hum Mol Genet. 2006;15:2200–2209. doi: 10.1093/hmg/ddl145. [DOI] [PubMed] [Google Scholar]
349. Pin JP, Bettler B. Organization and functions of mGlu and GABAB receptor complexes. Nature. 2016;540:60–68. doi: 10.1038/nature20566. [DOI] [PubMed] [Google Scholar]
350. Piret SE, Gorvin CM, Pagnamenta AT, Howles SA, Cranston T, Rust N, Nesbit MA, Glaser B, Taylor JC, Buchs AE, Hannan FM, Thakker RV. Identification of a G-Protein subunit-α11 gain-of-function mutation, Val340Met, in a family with autosomal dominant hypocalcemia type 2 (ADH2) J Bone Miner Res. 2016;31:1207–1214. doi: 10.1002/jbmr.2797. [DOI] [PMC free article] [PubMed] [Google Scholar]
351. Piret SE, Thakker RV. Mouse models for inherited endocrine and metabolic disorders. J Endocrinol. 2011;211:211–230. doi: 10.1530/JOE-11-0193. [DOI] [PubMed] [Google Scholar]
352. Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75:1297–1303. doi: 10.1016/0092-8674(93)90617-y. [DOI] [PubMed] [Google Scholar]
353. Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet. 1994;8:303–307. doi: 10.1038/ng1194-303. [DOI] [PubMed] [Google Scholar]
354. Procino G, Mastrofrancesco L, Tamma G, Lasorsa DR, Ranieri M, Stringini G, Emma F, Svelto M, Valenti G. Calcium-sensing receptor and aquaporin 2 interplay in hypercalciuria- associated renal concentrating defect in humans. An in vivo and in vitro study. PLoS One. 2012;7:e33145. doi: 10.1371/journal.pone.0033145. [DOI] [PMC free article] [PubMed] [Google Scholar]
355. Promkan M, Liu G, Patmasiriwat P, Chakrabarty S. BRCA1 suppresses the expression of survivin and promotes sensitivity to paclitaxel through the calcium sensing receptor (CaSR) in human breast cancer cells. Cell Calcium. 2011;49:79–88. doi: 10.1016/j.ceca.2011.01.003. [DOI] [PubMed] [Google Scholar]
356. Quinn SJ, Bai M, Brown EM. pH Sensing by the calcium-sensing receptor. J Biol Chem. 2004;279:37241–37249. doi: 10.1074/jbc.M404520200. [DOI] [PubMed] [Google Scholar]
357. Quinn SJ, Kifor O, Trivedi S, Diaz R, Vassilev P, Brown EM. Sodium and ionic strength sensing by the calcium receptor. J Biol Chem. 1998;273:19579–19586. doi: 10.1074/jbc.273.31.19579. [DOI] [PubMed] [Google Scholar]
358. Quinn SJ, Ye CP, Diaz R, Kifor O, Bai M, Vassilev P, Brown E. The Ca2+-sensing receptor: a target for polyamines. Am J Physiol. 1997;273:C1315–1323. doi: 10.1152/ajpcell.1997.273.4.C1315. [DOI] [PubMed] [Google Scholar]
359. Racke FK, Hammerland LG, Dubyak GR, Nemeth EF. Functional expression of the parathyroid cell calcium receptor in Xenopus oocytes. FEBS Lett. 1993;333:132–136. doi: 10.1016/0014-5793(93)80390-g. [DOI] [PubMed] [Google Scholar]
360. Ramirez JA, Goodman WG, Gornbein J, Menezes C, Moulton L, Segre GV, Salusky IB. Direct in vivo comparison of calcium-regulated parathyroid hormone secretion in normal volunteers and patients with secondary hyperparathyroidism. J Clin Endocrinol Metab. 1993;76:1489–1494. doi: 10.1210/jcem.76.6.8501155. [DOI] [PubMed] [Google Scholar]
361. Rasmussen AQ, Jorgensen NR, Schwarz P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series. J Med Case Rep. 2011;5:564. doi: 10.1186/1752-1947-5-564. [DOI] [PMC free article] [PubMed] [Google Scholar]
362. Ratnam AV, Bikle DD, Cho JK. 1,25 dihydroxyvitamin D3 enhances the calcium response of keratinocytes. J Cell Physiol. 1999;178:188–196. doi: 10.1002/(SICI)1097-4652(199902)178:2<188::AID-JCP8>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
363. Ray JM, Squires PE, Curtis SB, Meloche MR, Buchan AM. Expression of the calcium- sensing receptor on human antral gastrin cells in culture. J Clin Invest. 1997;99:2328–2333. doi: 10.1172/JCI119413. [DOI] [PMC free article] [PubMed] [Google Scholar]
364. Ray K. Calcium-sensing receptor: Trafficking, endocytosis, recycling, and importance of interacting proteins. Prog Mol Biol Transl Sci. 2015;132:127–150. doi: 10.1016/bs.pmbts.2015.02.006. [DOI] [PubMed] [Google Scholar]
365. Ray K, Clapp P, Goldsmith PK, Spiegel AM. Identification of the sites of N-linked glycosylation on the human calcium receptor and assessment of their role in cell surface expression and signal transduction. J Biol Chem. 1998;273:34558–34567. doi: 10.1074/jbc.273.51.34558. [DOI] [PubMed] [Google Scholar]
366. Ray K, Hauschild BC, Steinbach PJ, Goldsmith PK, Hauache O, Spiegel AM. Identification of the cysteine residues in the amino-terminal extracellular domain of the human Ca(2+) receptor critical for dimerization. Implications for function of monomeric Ca(2+) receptor. J Biol Chem. 1999;274:27642–27650. doi: 10.1074/jbc.274.39.27642. [DOI] [PubMed] [Google Scholar]
367. Ray K, Northup J. Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor. J Biol Chem. 2002;277:18908–18913. doi: 10.1074/jbc.M202113200. [DOI] [PubMed] [Google Scholar]
368. Reginster JY, Seeman E, De Vernejoul MC, Adami S, Compston J, Phenekos C, Devogelaer JP, Curiel MD, Sawicki A, Goemaere S, Sorensen OH, Felsenberg D, Meunier PJ. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:2816–2822. doi: 10.1210/jc.2004-1774. [DOI] [PubMed] [Google Scholar]
369. Reh CM, Hendy GN, Cole DE, Jeandron DD. Neonatal hyperparathyroidism with a heterozygous calcium-sensing receptor (CaSR) R185Q mutation: clinical benefit from cinacalcet. J Clin Endocrinol Metab. 2011;96:E707–712. doi: 10.1210/jc.2010-1306. [DOI] [PubMed] [Google Scholar]
370. Renkema KY, Velic A, Dijkman HB, Verkaart S, van der Kemp AW, Nowik M, Timmermans K, Doucet A, Wagner CA, Bindels RJ, Hoenderop JG. The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. J Am Soc Nephrol. 2009;20:1705–1713. doi: 10.1681/ASN.2008111195. [DOI] [PMC free article] [PubMed] [Google Scholar]
371. Rey O, Chang W, Bikle D, Rozengurt N, Young SH, Rozengurt E. Negative cross-talk between calcium-sensing receptor and β-catenin signaling systems in colonic epithelium. J Biol Chem. 2012;287:1158–1167. doi: 10.1074/jbc.M111.274589. [DOI] [PMC free article] [PubMed] [Google Scholar]
372. Rey O, Young SH, Papazyan R, Shapiro MS, Rozengurt E. Requirement of the TRPC1 cation channel in the generation of transient Ca2+ oscillations by the calcium-sensing receptor. J Biol Chem. 2006;281:38730–38737. doi: 10.1074/jbc.M605956200. [DOI] [PubMed] [Google Scholar]
373. Rey O, Young SH, Yuan J, Slice L, Rozengurt E. Amino acid-stimulated Ca2+ oscillations produced by the Ca2+-sensing receptor are mediated by a phospholipase C/inositol 1,4,5-trisphosphate-independent pathway that requires G12, Rho, filamin-A, and the actin cytoskeleton. J Biol Chem. 2005;280:22875–22882. doi: 10.1074/jbc.M503455200. [DOI] [PubMed] [Google Scholar]
374. Reyes-Ibarra AP, Garcia-Regalado A, Ramirez-Rangel I, Esparza-Silva AL, Valadez-Sanchez M, Vazquez-Prado J, Reyes-Cruz G. Calcium-sensing receptor endocytosis links extracellular calcium signaling to parathyroid hormone-related peptide secretion via a Rab11a-dependent and AMSH-sensitive mechanism. Mol Endocrinol. 2007;21:1394–1407. doi: 10.1210/me.2006-0523. [DOI] [PubMed] [Google Scholar]
375. Riccardi D, Hall AE, Chattopadhyay N, Xu JZ, Brown EM, Hebert SC. Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol. 1998;274:F611–622. doi: 10.1152/ajprenal.1998.274.3.F611. [DOI] [PubMed] [Google Scholar]
376. Riccardi D, Kemp PJ. The calcium-sensing receptor beyond extracellular calcium homeostasis: conception, development, adult physiology, and disease. Annu Rev Physiol. 2012;74:271–297. doi: 10.1146/annurev-physiol-020911-153318. [DOI] [PubMed] [Google Scholar]
377. Riccardi D, Park J, Lee WS, Gamba G, Brown EM, Hebert SC. Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing receptor. Proc Natl Acad Sci USA. 1995;92:131–135. doi: 10.1073/pnas.92.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
378. Riccardi D, Valenti G. Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol. 2016;12:414–425. doi: 10.1038/nrneph.2016.59. [DOI] [PubMed] [Google Scholar]
379. Rietsema S, Eelderink C, Joustra ML, van Vliet IMY, van Londen M, Corpeleijn E, Singh-Povel CM, Geurts JMW, Kootstra-Ros JE, Westerhuis R, Navis G, Bakker SJL. Effect of high compared with low dairy intake on blood pressure in overweight middle-aged adults: results of a randomized crossover intervention study. Am J Clin Nutr. 2019;110:340–348. doi: 10.1093/ajcn/nqz116. [DOI] [PMC free article] [PubMed] [Google Scholar]
380. Ritter CS, Haughey BH, Armbrecht HJ, Brown AJ. Distribution and regulation of the 25- hydroxyvitamin D3 1α-hydroxylase in human parathyroid glands. J Steroid Biochem Mol Biol. 2012;130:73–80. doi: 10.1016/j.jsbmb.2012.01.010. [DOI] [PubMed] [Google Scholar]
381. Roberts MS, Gafni RI, Brillante B, Guthrie LC, Streit J, Gash D, Gelb J, Krusinska E, Brennan SC, Schepelmann M, Riccardi D, Bin Khayat ME, Ward DT, Nemeth EF, Rosskamp R, Collins MT. Treatment of Autosomal Dominant Hypocalcemia Type 1 with the Calcilytic NPSP795 (SHP635) J Bone Miner Res. 2019;34:1609–1618. doi: 10.1002/jbmr.3747. [DOI] [PMC free article] [PubMed] [Google Scholar]
382. Rodriguez L, Tu C, Cheng Z, Chen TH, Bikle D, Shoback D, Chang W. Expression and functional assessment of an alternatively spliced extracellular Ca2+-sensing receptor in growth plate chondrocytes. Endocrinology. 2005;146:5294–5303. doi: 10.1210/en.2005-0256. [DOI] [PubMed] [Google Scholar]
383. Rodriguez-Hernandez CJ, Mateo-Lozano S, Garcia M, Casala C, Brianso F, Castrejon N, Rodriguez E, Sunol M, Carcaboso AM, Lavarino C, Mora J, de Torres C. Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens. Oncotarget. 2016;7:16112–16129. doi: 10.18632/oncotarget.7448. [DOI] [PMC free article] [PubMed] [Google Scholar]
384. Romano C, Yang WL, O'Malley KL. Metabotropic glutamate receptor 5 is a disulfide- linked dimer. J Biol Chem. 1996;271:28612–28616. doi: 10.1074/jbc.271.45.28612. [DOI] [PubMed] [Google Scholar]
385. Rorsman P, Braun M, Zhang Q. Regulation of calcium in pancreatic α- and β-cells in health and disease. Cell Calcium. 2012;51:300–308. doi: 10.1016/j.ceca.2011.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
386. Roszko KL, Bi R, Gorvin CM, Bräuner-Osborne H, Xiong XF, Inoue A, Thakker RV, Stromgaard K, Gardella T, Mannstadt M. Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors. JCI Insight. 2017;2:e91079. doi: 10.1172/jci.insight.91079. [DOI] [PMC free article] [PubMed] [Google Scholar]
387. Ruat M, Molliver ME, Snowman AM, Snyder SH. Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals. Proc Natl Acad Sci USA. 1995;92:3161–3165. doi: 10.1073/pnas.92.8.3161. [DOI] [PMC free article] [PubMed] [Google Scholar]
388. Ruat M, Snowman AM, Hester LD, Snyder SH. Cloned and expressed rat Ca2+-sensing receptor. J Biol Chem. 1996;271:5972–5975. doi: 10.1074/jbc.271.11.5972. [DOI] [PubMed] [Google Scholar]
389. Rus R, Haag C, Bumke-Vogt C, Bahr V, Mayr B, Mohlig M, Schulze E, Frank-Raue K, Raue F, Schofl C. Novel inactivating mutations of the calcium-sensing receptor: the calcimimetic NPS R-568 improves signal transduction of mutant receptors. J Clin Endocrinol Metab. 2008;93:4797–4803. doi: 10.1210/jc.2008-1076. [DOI] [PubMed] [Google Scholar]
390. Rybchyn MS, Green WL, Conigrave AD, Mason RS. Involvement of both GPRC6A and the calcium-sensing receptor in strontium ranelate-induced osteoclastogenic signal expression and replication in primary human osteoblasts. Bone. 2009;44:S317–S317. [Google Scholar]
391. Rybchyn MS, Islam KS, Brennan-Speranza TC, Cheng Z, Brennan SC, Chang W, Mason RS, Conigrave AD. Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent β-catenin stabilization in osteoblasts. J Biol Chem. 2019;294:16337–16350. doi: 10.1074/jbc.RA118.006587. [DOI] [PMC free article] [PubMed] [Google Scholar]
392. Rybchyn MS, Slater M, Conigrave AD, Mason RS. An Akt-dependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate-induced osteogenic effects in human osteoblasts. J Biol Chem. 2011;286:23771–23779. doi: 10.1074/jbc.M111.251116. [DOI] [PMC free article] [PubMed] [Google Scholar]
393. Saidak Z, Boudot C, Abdoune R, Petit L, Brazier M, Mentaverri R, Kamel S. Extracellular calcium promotes the migration of breast cancer cells through the activation of the calcium sensing receptor. Exp Cell Res. 2009;315:2072–2080. doi: 10.1016/j.yexcr.2009.03.003. [DOI] [PubMed] [Google Scholar]
394. Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest. 1997;99:1399–1405. doi: 10.1172/JCI119299. [DOI] [PMC free article] [PubMed] [Google Scholar]
395. Santa Maria C, Cheng Z, Li A, Wang J, Shoback D, Tu CL, Chang W. Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism. Semin Cell Dev Biol. 2016;49:11–23. doi: 10.1016/j.semcdb.2015.12.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
396. Santa Maria C, Li A, Cheng Z, Song F, Shoback D, Tu C. ASBMR Annual Meeting. Washington State Convention Center: 2015. Skeletal anabolism by concurrently targeting the PTH1R and CaSR. [Google Scholar]
397. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zugel U, Bikle DD, Modlin RL, Gallo RL. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007;117:803–811. doi: 10.1172/JCI30142. [DOI] [PMC free article] [PubMed] [Google Scholar]
398. Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graca J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, Edwards DH, Kemp PJ, Riccardi D. The vascular Ca2+- sensing receptor regulates blood vessel tone and blood pressure. Am J Physiol Cell Physiol. 2016;310:C193–204. doi: 10.1152/ajpcell.00248.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
399. Sethi BK, Nagesh VS, Kelwade J, Parekh H, Dukle V. Utility of cinacalcet in familial hypocalciuric hypercalcemia. Indian J Endocrinol Metab. 2017;21:362–363. doi: 10.4103/2230-8210.202034. [DOI] [PMC free article] [PubMed] [Google Scholar]
400. Shalhoub V, Grisanti M, Padagas J, Scully S, Rattan A, Qi M, Varnum B, Vezina C, Lacey D, Martin D. In vitro studies with the calcimimetic, cinacalcet HCl, on normal human adult osteoblastic and osteoclastic cells. Crit Rev Eukaryot Gene Expr. 2003;13:89–106. doi: 10.1615/critreveukaryotgeneexpr.v13.i24.30. [DOI] [PubMed] [Google Scholar]
401. Shams-White MM, Chung M, Du M, Fu Z, Insogna KL, Karlsen MC, LeBoff MS, Shapses SA, Sackey J, Wallace TC, Weaver CM. Dietary protein and bone health: a systematic review and meta-analysis from the National Osteoporosis Foundation. Am J Clin Nutr. 2017;105:1528–1543. doi: 10.3945/ajcn.116.145110. [DOI] [PubMed] [Google Scholar]
402. Shcherbakova I, Huang G, Geoffroy OJ, Nair SK, Swierczek K, Balandrin MF, Fox J, Heaton WL, Conklin RL. Design, new synthesis, and calcilytic activity of substituted 3H- pyrimidin-4-ones. Bioorg Med Chem Lett. 2005;15:2537–2540. doi: 10.1016/j.bmcl.2005.03.054. [DOI] [PubMed] [Google Scholar]
403. Shinagawa Y, Inoue T, Katsushima T, Kiguchi T, Ikenogami T, Ogawa N, Fukuda K, Hirata K, Harada K, Takagi M, Nakagawa T, Kimura S, Matsuo Y, Maekawa M, Hayashi M, Soejima Y, Takahashi M, Shindo M, Hashimoto H. Discovery of a potent and short-acting oral calcilytic with a pulsatile secretion of parathyroid hormone. ACS medicinal chemistry letters. 2011;2:238–242. doi: 10.1021/ml100268k. [DOI] [PMC free article] [PubMed] [Google Scholar]
404. Shoback DM, Membreno LA, McGhee JG. High calcium and other divalent cations increase inositol trisphosphate in bovine parathyroid cells. Endocrinology. 1988;123:382–389. doi: 10.1210/endo-123-1-382. [DOI] [PubMed] [Google Scholar]
405. Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 1988;175:266–276. doi: 10.1016/0014-4827(88)90191-7. [DOI] [PubMed] [Google Scholar]
406. Smajilovic S, Sheykhzade M, Holmegard HN, Haunso S, Tfelt-Hansen J. Calcimimetic, AMG 073, induces relaxation on isolated rat aorta. Vascul Pharmacol. 2007;47:222–228. doi: 10.1016/j.vph.2007.06.010. [DOI] [PubMed] [Google Scholar]
407. Smajilovic S, Wellendorph P, Bräuner-Osborne H. Promiscuous seven transmembrane receptors sensing L-α-amino acids. Curr Pharm Des. 2014;20:2693–2702. doi: 10.2174/13816128113199990576. [DOI] [PubMed] [Google Scholar]
408. Soda K, Kano Y, Sakuragi M, Takao K, Lefor A, Konishi F. Long-term oral polyamine intake increases blood polyamine concentrations. J Nutr Sci Vitaminol (Tokyo) 2009;55:361–366. doi: 10.3177/jnsv.55.361. [DOI] [PubMed] [Google Scholar]
409. Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN. The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics. 2012;Chapter 1:13. doi: 10.1002/0471250953.bi0113s39. Unit1. [DOI] [PubMed] [Google Scholar]
410. Stepanchick A, McKenna J, McGovern O, Huang Y, Breitwieser GE. Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell Physiol Biochem. 2010;26:363–374. doi: 10.1159/000320560. [DOI] [PMC free article] [PubMed] [Google Scholar]
411. Sun X, Tang L, Winesett S, Chang W, Cheng SX. Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons. Life Sci. 2018;194:49–58. doi: 10.1016/j.lfs.2017.12.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
412. Suzuki K, Lavaroni S, Mori A, Okajima F, Kimura S, Katoh R, Kawaoi A, Kohn L. Thyroid transcription factor 1 is calcium modulated and coordinately regulates genes involved in calcium homeostasis in C cells. Mol Cell Biol. 1998;18:7410–7422. doi: 10.1128/mcb.18.12.7410. [DOI] [PMC free article] [PubMed] [Google Scholar]
413. Tang H, Yamamura A, Yamamura H, Song S, Fraidenburg DR, Chen J, Gu Y, Pohl NM, Zhou T, Jimenez-Perez L, Ayon RJ, et al. Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2016a;310:L846–859. doi: 10.1152/ajplung.00050.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
414. Tang L, Cheng CY, Sun X, Pedicone AJ, Mahamadzadeh M, Cheng SX. The extracellular calcium-sensing receptor in the intestine: Evidence for regulation of colonic absorption, secretion, motility, and immunity. Front Physiol. 2016b;7:245. doi: 10.3389/fphys.2016.00245. [DOI] [PMC free article] [PubMed] [Google Scholar]
415. Tang L, Jiang L, McIntyre ME, Petrova E, Cheng SX. Calcimimetic acts on enteric neuronal CaSR to reverse cholera toxin-induced intestinal electrolyte secretion. Sci Rep. 2018;8 doi: 10.1038/s41598-018-26171-4. 7851. [DOI] [PMC free article] [PubMed] [Google Scholar]
416. Tang L, Peng M, Liu L, Chang W, Binder HJ, Cheng SX. Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon. Am J Physiol Gastrointest Liver Physiol. 2015;308:G874–883. doi: 10.1152/ajpgi.00341.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
417. Tatsumi R, Komaba H, Kanai G, Miyakogawa T, Sawada K, Kakuta T, Fukagawa M. Cinacalcet induces apoptosis in parathyroid cells in patients with secondary hyperparathyroidism: histological and cytological analyses. Nephron Clin Pract. 2013;124:224–231. doi: 10.1159/000357951. [DOI] [PubMed] [Google Scholar]
418. Temal T, Jary H, Auberval M, Lively S, Guedin D, Vevert JP, Deprez P. New potent calcimimetics: I. Discovery of a series of novel trisubstituted ureas. Bioorg Med Chem Lett. 2013;23:2451–2454. doi: 10.1016/j.bmcl.2013.01.078. [DOI] [PubMed] [Google Scholar]
419. Tenhola S, Hendy GN, Valta H, Canaff L, Lee BS, Wong BY, Valimaki MJ, Cole DE, Makitie O. Cinacalcet treatment in an adolescent with concurrent 22q11.2 deletion syndrome and FHH3 caused by AP2S1 mutation. J Clin Endocrinol Metab. 2015;100:2515–2518. doi: 10.1210/jc.2015-1518. [DOI] [PubMed] [Google Scholar]
420. Tenhola S, Voutilainen R, Reyes M, Toiviainen-Salo S, Juppner H, Makitie O. Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. Eur J Endocrinol. 2016;175:211–218. doi: 10.1530/EJE-16-0109. [DOI] [PMC free article] [PubMed] [Google Scholar]
421. Tfelt-Hansen J, MacLeod RJ, Chattopadhyay N, Yano S, Quinn S, Ren X, Terwilliger EF, Schwarz P, Brown EM. Calcium-sensing receptor stimulates PTHrP release by pathways dependent on PKC, p38 MAPK, JNK, and ERK1/2 in H-500 cells. Am J Physiol. 2003;285:E329–E337. doi: 10.1152/ajpendo.00489.2002. [DOI] [PubMed] [Google Scholar]
422. Thakore P, Ho WS. Vascular actions of calcimimetics: role of Ca2(+) -sensing receptors versus Ca2(+) influx through L-type Ca2(+) channels. Br J Pharmacol. 2011;162:749–762. doi: 10.1111/j.1476-5381.2010.01079.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
423. Thomsen AR, Hvidtfeldt M, Bräuner-Osborne H. Biased agonism of the calcium- sensing receptor. Cell Calcium. 2012a;51:107–116. doi: 10.1016/j.ceca.2011.11.009. [DOI] [PubMed] [Google Scholar]
424. Thomsen AR, Worm J, Jacobsen SE, Stahlhut M, Latta M, Bräuner-Osborne H. Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. J Pharmacol Exp Ther. 2012b;343:638–649. doi: 10.1124/jpet.112.197210. [DOI] [PMC free article] [PubMed] [Google Scholar]
425. Toka HR, Al-Romaih K, Koshy JM, DiBartolo S, Kos CH, Quinn SJ, Curhan GC, Mount DB, Brown EM, Pollak MR. Deficiency of the calcium-sensing receptor in the kidney causes parathyroid hormone-independent hypocalciuria. J Am Soc Nephrol. 2012;23:1879–1890. doi: 10.1681/ASN.2012030323. [DOI] [PMC free article] [PubMed] [Google Scholar]
426. Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S. Action of molecular switches in GPCRs--theoretical and experimental studies. Curr Med Chem. 2012;19:1090–1109. doi: 10.2174/092986712799320556. [DOI] [PMC free article] [PubMed] [Google Scholar]
427. Tsuchiya D, Kunishima N, Kamiya N, Jingami H, Morikawa K. Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+ Proc Natl Acad Sci USA. 2002;99:2660–2665. doi: 10.1073/pnas.052708599. [DOI] [PMC free article] [PubMed] [Google Scholar]
428. Tsutsumi M, Goto M, Denda M. Dynamics of intracellular calcium in cultured human keratinocytes after localized cell damage. Exp Dermatol. 2013;22:367–369. doi: 10.1111/exd.12136. [DOI] [PubMed] [Google Scholar]
429. Tu CL, Bikle DD. Role of the calcium-sensing receptor in calcium regulation of epidermal differentiation and function. Best Pract Res Clin Endocrinol Metab. 2013;27:415–427. doi: 10.1016/j.beem.2013.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
430. Tu CL, Celli A, Mauro T, Chang W. Calcium-sensing receptor regulates epidermal intracellular Ca2+ signaling and re-epithelialization after wounding. J Invest Dermatol. 2019;139:919–929. doi: 10.1016/j.jid.2018.09.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
431. Tu CL, Chang WH, Xie ZJ, Bikle DD. Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes. J Biol Chem. 2008;283:3519–3528. doi: 10.1074/jbc.M708318200. [DOI] [PubMed] [Google Scholar]
432. Tu CL, Crumrine DA, Man MQ, Chang W, Elalieh H, You M, Elias PM, Bikle DD. Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function. The Journal of investigative dermatology. 2012;132:2350–2359. doi: 10.1038/jid.2012.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
433. Tu Q, Pi M, Karsenty G, Simpson L, Liu S, Quarles LD. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest. 2003;111:1029–1037. doi: 10.1172/JCI17054. [DOI] [PMC free article] [PubMed] [Google Scholar]
434. Turksen K, Troy TC. Overexpression of the calcium sensing receptor accelerates epidermal differentiation and permeability barrier formation in vivo. Mech Dev. 2003;120:733–744. doi: 10.1016/s0925-4773(03)00045-5. [DOI] [PubMed] [Google Scholar]
435. van den Berg MP, Meurs H, Gosens R. Targeting arginase and nitric oxide metabolism in chronic airway diseases and their co-morbidities. Curr Opin Pharmacol. 2018;40:126–133. doi: 10.1016/j.coph.2018.04.010. [DOI] [PubMed] [Google Scholar]
436. Vancleef L, Van Den Broeck T, Thijs T, Steensels S, Briand L, Tack J, Depoortere I. Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell. Sci Rep. 2015;5 doi: 10.1038/srep15725. 15725. [DOI] [PMC free article] [PubMed] [Google Scholar]
437. VanHouten J, Dann P, McGeoch G, Brown EM, Krapcho K, Neville M, Wysolmerski JJ. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest. 2004;113:598–608. doi: 10.1172/JCI18776. [DOI] [PMC free article] [PubMed] [Google Scholar]
438. VanHouten JN, Neville MC, Wysolmerski JJ. The calcium-sensing receptor regulates plasma membrane calcium adenosine triphosphatase isoform 2 activity in mammary epithelial cells: a mechanism for calcium-regulated calcium transport into milk. Endocrinology. 2007;148:5943–5954. doi: 10.1210/en.2007-0850. [DOI] [PMC free article] [PubMed] [Google Scholar]
439. VanHouten JN, Wysolmerski JJ. Transcellular calcium transport in mammary epithelial cells. J Mammary Gland Biol Neoplasia. 2007;12:223–235. doi: 10.1007/s10911-007-9057-1. [DOI] [PubMed] [Google Scholar]
440. Vanhouten JN, Wysolmerski JJ. The calcium-sensing receptor in the breast. Best Pract Res Clin Endocrinol Metab. 2013;27:403–414. doi: 10.1016/j.beem.2013.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
441. Vargas-Poussou R, Mansour-Hendili L, Baron S, Bertocchio JP, Travers C, Simian C, Treard C, Baudouin V, Beltran S, Broux F, Camard O, Cloarec S, Cormier C, Debussche X, Dubosclard E, Eid C, Haymann JP, Romuald Kiando S, Kuhn JM, Lefort G, Linglart A, Lucas-Pouliquen B, Macher MA, Maruani G, Ouzounian S, Polak M, Requeda E, Robier D, Silve C, Souberbielle JC, Tack I, Vezzosi D, Jeunemaitre X, Houillier P. Familial hypocalciuric hypercalcemia types 1 and 3 and primary hyperparathyroidism: similarities and differences. J Clin Endocrinol Metab. 2016;101:2185–2195. doi: 10.1210/jc.2015-3442. [DOI] [PubMed] [Google Scholar]
442. Vezzoli G, Scillitani A, Corbetta S, Terranegra A, Dogliotti E, Guarnieri V, Arcidiacono T, Paloschi V, Rainone F, Eller-Vainicher C, Borghi L, Nouvenne A, Guerra A, Meschi T, Allegri F, Cusi D, Spada A, Cole DE, Hendy GN, Spotti D, Soldati L. Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism. Eur J Endocrinol. 2011;164:421–427. doi: 10.1530/EJE-10-0915. [DOI] [PubMed] [Google Scholar]
443. Vizard TN, O'Keeffe GW, Gutierrez H, Kos CH, Riccardi D, Davies AM. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat Neurosci. 2011;11:285–291. doi: 10.1038/nn2044. [DOI] [PMC free article] [PubMed] [Google Scholar]
444. Walter S, Baruch A, Dong J, Tomlinson JE, Alexander ST, Janes J, Hunter T, Yin Q, Maclean D, Bell G, Mendel DB, Johnson RM, Karim F. Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther. 2013;346:229–240. doi: 10.1124/jpet.113.204834. [DOI] [PubMed] [Google Scholar]
445. Wang L, Widatalla SE, Whalen DS, Ochieng J, Sakwe AM. Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients. BMC Cancer. 2017;17:511. doi: 10.1186/s12885-017-3502-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
446. Wang M, Yao Y, Kuang D, Hampson DR. Activation of family C G-protein-coupled receptors by the tripeptide glutathione. J Biol Chem. 2006;281:8864–8870. doi: 10.1074/jbc.M512865200. [DOI] [PubMed] [Google Scholar]
447. Wang X, Kirberger M, Qiu F, Chen G, Yang JJ. Towards predicting Ca2+-binding sites with different coordination numbers in proteins with atomic resolution. Proteins. 2009;75:787–798. doi: 10.1002/prot.22285. [DOI] [PMC free article] [PubMed] [Google Scholar]
448. Wang X, Zhao K, Kirberger M, Wong H, Chen G, Yang JJ. Analysis and prediction of calcium-binding pockets from apo-protein structures exhibiting calcium-induced localized conformational changes. Protein Sci. 2010;19:1180–1190. doi: 10.1002/pro.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
449. Wang Y, Chandra R, Samsa LA, Gooch B, Fee BE, Cook JM, Vigna SR, Grant AO, Liddle RA. Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J Physiol Gastrointest Liver Physiol. 2011;300:G528–537. doi: 10.1152/ajpgi.00387.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
450. Ward DT, Brown EM, Harris HW. Disulfide bonds in the extracellular calcium- polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro. J Biol Chem. 1998;273:14476–14483. doi: 10.1074/jbc.273.23.14476. [DOI] [PubMed] [Google Scholar]
451. Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet. 2002;360:692–694. doi: 10.1016/S0140-6736(02)09842-2. [DOI] [PubMed] [Google Scholar]
452. Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, Mao JH, Appella E, Balmain A, Huang EJ. HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc Natl Acad Sci USA. 2007;104:13040–13045. doi: 10.1073/pnas.0703213104. [DOI] [PMC free article] [PubMed] [Google Scholar]
453. Wellendorph P, Bräuner-Osborne H. Molecular basis for amino acid sensing by family C G protein-coupled receptors. Br J Pharmacol. 2009;156:869–884. doi: 10.1111/j.1476-5381.2008.00078.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
454. Wettschureck N, Lee E, Libutti SK, Offermanns S, Robey PG, Spiegel AM. Parathyroid- specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor. Mol Endocrinol. 2007;21:274–280. doi: 10.1210/me.2006-0110. [DOI] [PubMed] [Google Scholar]
455. White E, McKenna J, Cavanaugh A, Breitwieser GE. Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Mol Endocrinol. 2009;23:1115–1123. doi: 10.1210/me.2009-0041. [DOI] [PMC free article] [PubMed] [Google Scholar]
456. Wolf P, Krssak M, Winhofer Y, Anderwald CH, Zwettler E, Just Kukurova I, Gessl A, Trattnig S, Luger A, Baumgartner-Parzer S, Krebs M. Cardiometabolic phenotyping of patients with familial hypocalcuric hypercalcemia. J Clin Endocrinol Metab. 2014;99:E1721–1726. doi: 10.1210/jc.2014-1541. [DOI] [PubMed] [Google Scholar]
457. Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344:58–64. doi: 10.1126/science.1249489. [DOI] [PMC free article] [PubMed] [Google Scholar]
458. Wu W, Zhou HR, Bursian SJ, Link JE, Pestka JJ. Calcium-sensing receptor and transient receptor ankyrin-1 mediate emesis induction by deoxynivalenol (Vomitoxin) Toxicol Sci. 2017;155:32–42. doi: 10.1093/toxsci/kfw191. [DOI] [PMC free article] [PubMed] [Google Scholar]
459. Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97:2947–2956. doi: 10.1210/jc.2012-2142. [DOI] [PMC free article] [PubMed] [Google Scholar]
460. Xie R, Xu J, Xiao Y, Wu J, Wan H, Tang B, Liu J, Fan Y, Wang S, Wu Y, Dong TX, Zhu MX, Carethers JM, Dong H, Yang S. Calcium promotes human gastric cancer via a novel coupling of calcium-sensing receptor and TRPV4 channel. Cancer Res. 2017;77:6499–6512. doi: 10.1158/0008-5472.CAN-17-0360. [DOI] [PubMed] [Google Scholar]
461. Yamada S, Tokumoto M, Taniguchi M, Toyonaga J, Suehiro T, Eriguchi R, Fujimi S, Ooboshi H, Kitazono T, Tsuruya K. Two years of cinacalcet hydrochloride treatment decreased parathyroid gland volume and serum parathyroid hormone level in hemodialysis patients with advanced secondary hyperparathyroidism. Ther Apher Dial. 2015;19:367–377. doi: 10.1111/1744-9987.12292. [DOI] [PubMed] [Google Scholar]
462. Yamamoto M, Akatsu T, Nagase T, Ogata E. Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of- function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders? J Clin Endocrinol Metab. 2000;85:4583–4591. doi: 10.1210/jcem.85.12.7035. [DOI] [PubMed] [Google Scholar]
463. Yang C, Rybchyn MS, Conigrave AD, Mason RS. Role of Calcium sensing receptor (CaSR) modifiers in photoprotection. Wound Repair Regen. 2016;24:A16. [Google Scholar]
464. Yang W, Liu L, Masugi Y, Qian ZR, Nishihara R, Keum N, Wu K, Smith-Warner S, Ma Y, Nowak JA, Momen-Heravi F, Zhang L, Bowden M, Morikawa T, Silva AD, Wang M, Chan AT, Fuchs CS, Meyerhardt JA, Ng K, Giovannucci E, Ogino S, Zhang X. Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR) Gut. 2017;67:1475–1483. doi: 10.1136/gutjnl-2017-314163. [DOI] [PMC free article] [PubMed] [Google Scholar]
465. Yang Y, Wang B. PTH1R-CaSR Cross Talk: New Treatment Options for Breast Cancer Osteolytic Bone Metastases. Int J Endocrinol. 2018;2018 doi: 10.1155/2018/7120979. 7120979. [DOI] [PMC free article] [PubMed] [Google Scholar]
466. Yarova PL, Stewart AL, Sathish V, Britt RD, Jr, Thompson MA, AP PL, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, JP TW, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015;7 doi: 10.1126/scitranslmed.aaa0282. 284ra260. [DOI] [PMC free article] [PubMed] [Google Scholar]
467. Ye C, Ho-Pao CL, Kanazirska M, Quinn S, Rogers K, Seidman CE, Seidman JG, Brown EM, Vassilev PM. Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors. J Neurosci Res. 1997a;47:547–554. doi: 10.1002/(sici)1097-4547(19970301)47:5<547::aid-jnr10>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
468. Ye C, Ho-Pao CL, Kanazirska M, Quinn S, Seidman CE, Seidman JG, Brown EM, Vassilev PM. Deficient cation channel regulation in neurons from mice with targeted disruption of the extracellular Ca2+-sensing receptor gene. Brain Res Bull. 1997b;44:75–84. doi: 10.1016/s0361-9230(97)00088-9. [DOI] [PubMed] [Google Scholar]
469. Ye C, Rogers K, Bai M, Quinn SJ, Brown EM, Vassilev PM. Agonists of the Ca(2+)- sensing receptor (CaR) activate nonselective cation channels in HEK293 cells stably transfected with the human CaR. Biochem Biophys Res Commun. 1996;226:572–579. doi: 10.1006/bbrc.1996.1396. [DOI] [PubMed] [Google Scholar]
470. Young SH, Rey O, Sinnett-Smith J, Rozengurt E. Intracellular Ca2+ oscillations generated via the Ca2+-sensing receptor are mediated by negative feedback by PKCalpha at Thr888. Am J Physiol Cell Physiol. 2014;306:C298–306. doi: 10.1152/ajpcell.00194.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
471. Youssef KK, Lapouge G, Bouvree K, Rorive S, Brohee S, Appelstein O, Larsimont JC, Sukumaran V, Van de Sande B, Pucci D, Dekoninck S, Berthe JV, Aerts S, Salmon I, del Marmol V, Blanpain C. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. Nat Cell Biol. 2012;14:1282–1294. doi: 10.1038/ncb2628. [DOI] [PubMed] [Google Scholar]
472. Zaidi M, Kerby J, Huang CL, Alam T, Rathod H, Chambers TJ, Moonga BS. Divalent cations mimic the inhibitory effect of extracellular ionised calcium on bone resorption by isolated rat osteoclasts: further evidence for a “calcium receptor”. J Cell Physiol. 1991;149:422–427. doi: 10.1002/jcp.1041490310. [DOI] [PubMed] [Google Scholar]
473. Zhang C, Huang Y, Jiang Y, Mulpuri N, Wei L, Hamelberg D, Brown EM, Yang JJ. Identification of an L-phenylalanine binding site enhancing the cooperative responses of the calcium-sensing receptor to calcium. J Biol Chem. 2014a;289:5296–5309. doi: 10.1074/jbc.M113.537357. [DOI] [PMC free article] [PubMed] [Google Scholar]
474. Zhang C, Zhang T, Zou J, Miller CL, Gorkhali R, Yang JY, Schilmiller A, Wang S, Huang K, Brown EM, Moremen KW, Hu J, Yang JJ. Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist. Sci Adv. 2016;2:e1600241. doi: 10.1126/sciadv.1600241. [DOI] [PMC free article] [PubMed] [Google Scholar]
475. Zhang C, Zhuo Y, Moniz HA, Wang S, Moremen KW, Prestegard JH, Brown EM, Yang JJ. Direct determination of multiple ligand interactions with the extracellular domain of the calcium-sensing receptor. J Biol Chem. 2014b;289:33529–33542. doi: 10.1074/jbc.M114.604652. [DOI] [PMC free article] [PubMed] [Google Scholar]
476. Zhang H, Kovacs-Nolan J, Kodera T, Eto Y, Mine Y. γ-Glutamyl cysteine and γ- glutamyl valine inhibit TNF-alpha signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor. Biochim Biophys Acta. 2015;1852:792–804. doi: 10.1016/j.bbadis.2014.12.023. [DOI] [PubMed] [Google Scholar]
477. Zhang M, Yang H, Wan X, Lu L, Zhang J, Zhang H, Ye T, Liu Q, Xie M, Liu X, Yu S, Guo S, Chang W, Wang M. Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR. J Bone Miner Res. 2018 doi: 10.1002/jbmr.3643. [DOI] [PMC free article] [PubMed] [Google Scholar]
478. Zhang M, Yang H, Wan X, Lu L, Zhang J, Zhang H, Ye T, Liu Q, Xie M, Liu X, Yu S, Guo S, Chang W, Wang M. Prevention of injury-induced osteoarthritis in rodent temporomandibular joint by targeting chondrocyte CaSR. J Bone Miner Res. 2019;34:726–738. doi: 10.1002/jbmr.3643. [DOI] [PMC free article] [PubMed] [Google Scholar]
479. Zhang Z, Jiang Y, Quinn SJ, Krapcho K, Nemeth EF, Bai M. L-Phenylalanine and NPS R-467 synergistically potentiate the function of the extracellular calcium-sensing receptor through distinct sites. J Biol Chem. 2002a;277:33736–33741. doi: 10.1074/jbc.M200978200. [DOI] [PubMed] [Google Scholar]
480. Zhang Z, Qiu W, Quinn SJ, Conigrave AD, Brown EM, Bai M. Three adjacent serines in the extracellular domains of the CaR are required for L-amino acid-mediated potentiation of receptor function. J Biol Chem. 2002b;277:33727–33735. doi: 10.1074/jbc.M200976200. [DOI] [PubMed] [Google Scholar]
481. Zhang Z, Sun S, Quinn SJ, Brown EM, Bai M. The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions. J Biol Chem. 2001;276:5316–5322. doi: 10.1074/jbc.M005958200. [DOI] [PubMed] [Google Scholar]
482. Zhao K, Wang X, Wong HC, Wohlhueter R, Kirberger MP, Chen G, Yang JJ. Predicting Ca2+ -binding sites using refined carbon clusters. Proteins. 2012;80:2666–2679. doi: 10.1002/prot.24149. [DOI] [PMC free article] [PubMed] [Google Scholar]
483. Zhao X, Xian Y, Wang C, Ding L, Meng X, Zhu W, Hang S. Calcium-sensing receptor- mediated L-tryptophan-induced secretion of cholecystokinin and glucose-dependent insulinotropic peptide in swine duodenum. J Vet Sci. 2018;19:179–187. doi: 10.4142/jvs.2018.19.2.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
484. Zhuang X, Northup JK, Ray K. Large putative PEST-like sequence motif at the carboxyl tail of human calcium receptor directs lysosomal degradation and regulates cell surface receptor level. J Biol Chem. 2012;287:4165–4176. doi: 10.1074/jbc.M111.271528. [DOI] [PMC free article] [PubMed] [Google Scholar]
485. Zinser GM, Sundberg JP, Welsh J. Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis. 2002;23:2103–2109. doi: 10.1093/carcin/23.12.2103. [DOI] [PubMed] [Google Scholar]
486. Zuo X, Sun L, Yin X, Gao J, Sheng Y, Xu J, Zhang J, He C, Qiu Y, Wen G, Tian H, Zheng X, Liu S, Wang W, Li W, Cheng Y, Liu L, Chang Y, Wang Z, Li Z, Li L, Wu J, Fang L, Shen C, Zhou F, Liang B, Chen G, Li H, Cui Y, Xu A, Yang X, Hao F, Xu L, Fan X, Li Y, Wu R, Wang X, Liu X, Zheng M, Song S, Ji B, Fang H, Yu J, Sun Y, Hui Y, Zhang F, Yang R, Yang S, Zhang X. Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis. Nat Commun. 2015;6 doi: 10.1038/ncomms7793. 6793. [DOI] [PMC free article] [PubMed] [Google Scholar]