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International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function - PubMed

Review

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Katie Leach et al. Pharmacol Rev. 2020 Jul.

Abstract

The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, γ-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca2+ o, an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via Gq/11, Gi/o, potentially G12/13, and even Gs in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. SIGNIFICANCE STATEMENT: The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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Figures

Figure 1
Figure 1. Key CaSR signaling pathways.

The CaSR primarily couples to Gq/11 and Gi/o proteins to mediate many of its physiological responses including PTH release. The CaSR may also couple to G12/13 but the physiological relevance of this is unknown, therefore G12/13 is semi-transparent in the figure. CaM, calmodulin; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; PI3K, phosphatidylinositol 3-kinase; PI4K, phosphatidylinositol 4-kinase; all other abbreviations are as described in the text.

Figure 2
Figure 2. Structural conformation of the CaSR

(A). Model of the CaSR based on homology with full length mGluR5 (PDB 6N51). The CaSR (cartoon ribbon) comprises an extracellular VFT domain, composed of lobe 1 (LB1, dark blue) and lobe 2 (LB2, teal), and a cysteine rich (CR) domain (yellow) anchored to the 7TM (orange). (B). Inactive ECD monomer (PDB 5K5T). The bilobed VFT adopts an open conformation revealing a conserved binding cleft between the two lobes. (C). Inactive ECD dimer (left, front view; right, side view). The CR domains of the inactive ECDs are separated. (D). Active ECD monomer (PDB 5K5S). Upon activation, the bilobed VFT closes the amino acid binding site, narrowing the cleft. E). Active ECD dimer (left, front view; right, side view). Upon activation, each protomer (orange and yellow) is drawn closer together.

Figure 3
Figure 3. Binding sites within the CaSR crystal structures.

ECD conformations of the (A) active (PDB 5K5S), and (B) inactive (PDB 5K5S) calcium bound structures; and the VFT conformations of the (C) active magnesium bound (PDB 5FBK) and (D) active magnesium and gadolinium bound (PDB 5FBH) structures. Crystal structures are shown as cartoon ribbon within the transparent molecular surface and colored as in Figure 2. Hydrogen bond interactions (dashed lines) of calcium (red spheres), magnesium (green spheres), and gadolinium (yellow spheres) with key residues or water molecules (black spheres), are shown for each proposed binding site.

Figure 4
Figure 4. CaSR snakeplot with residues linked to loss- and gain-of-function germline mutations.

Snake-plot of the CaSR showing the location of the ECD, 7TM, ICLs, ECLs and carboxy-terminus. Sites of loss- and gain-of-function germline mutations causing FHH1/NSHPT (red), ADH1/Bartter syndrome type V (green), or both FHH1/NSHPT and ADH1/Bartter syndrome type V (yellow), respectively. Snake-plot generated by GPCRdb (Munk et al., 2016) with data from the Human Gene Mutation Database (Stenson et al., 2012).

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