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The role of cyclic nucleotides in pituitary lactotroph functions - PubMed

  • ️Tue Jan 01 2013

Review

The role of cyclic nucleotides in pituitary lactotroph functions

Marek Kucka et al. Front Endocrinol (Lausanne). 2013.

Abstract

Lactotrophs are one of the five secretory anterior pituitary cell types specialized to synthesize and release prolactin. In vitro, these cells fire action potentials (APs) spontaneously and the accompanied Ca(2+) transients are of sufficient amplitude to keep the exocytotic pathway, the transcription of prolactin gene, and de novo hormone synthesis continuously active. Basal cyclic nucleotide production is also substantial in cultured cells but not critical for the APs secretion/transcription coupling in lactotrophs. However, elevated intracellular cAMP levels enhance the excitability of lactotrophs by stimulating the depolarizing non-selective cationic hyperpolarization-activated cyclic nucleotide-regulated and background channels, whereas cGMP inhibits it by activating Ca(2+)-controlled K(+) channels. Elevated cAMP also modulates prolactin release downstream of Ca(2+) influx by changing the kinetic of secretory pores: stimulate at low and inhibit at high concentrations. Induction of prolactin gene and lactotroph proliferation is also stimulated by elevated cAMP through protein kinase A. Together, these observations suggest that in lactotrophs cAMP exhibits complex regulatory effects on voltage-gated Ca(2+) influx and Ca(2+)-dependent cellular processes.

Keywords: cAMP; cGMP; calcium; fusion pores; lactotrophs; prolactin; protein kinase A.

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Figures

Figure 1
Figure 1

Characterization of cyclic nucleotide signaling pathways in rat anterior pituitary cells in vitro. (A–C) Effect of IBMX, a PDEs inhibitor, on cAMP (A), cGMP (B), and PRL (C) release by perifused pituitary cells. (D,E) Correlation between released and cell content cAMP (D) and cGMP (E) in cells in static cultures treated with variable concentrations of IBMX. R, coefficient of correlation. (F) The relationship between cAMP intracellular content and PRL release. (G–I) Effects of forskolin, an AC activator, on cAMP (G), cGMP (H), and PRL (I) release by perifused pituitary cells. (J) Effect of MK571, an inhibitor of MRP transporters, on cAMP release in perifused pituitary cells. (K) Correlation between NO levels and cGMP production in cells stimulated with increasing doses of DPTA, an NO donor. (L) Stimulation of basal PRL release with 8-Br-cAMP but not with 8-pCPT-2Me-cAMP, an Epac cAMP receptor agonist. Gray areas indicate the duration of application of drugs.

Figure 2
Figure 2

Electrical activity and Ca2+ signaling in pituitary lactotrophs in vitro. (A) Simultaneous measurements of effects of apomorphine, a D2 receptor agonist, on spontaneous firing of APs (top) and Ca2+ signaling (bottom). (B,C) Effects of forskolin, an activator of ACs (B), and 8-Br-cAMP, a cell-permeable cAMP analog (C), on electrical activity of lactotrophs. (D) Effects of 8-Br-cAMP and Rp-cAMPs, a PKA inhibitor, on the frequency of APs in spontaneously firing lactotrophs. (E) Whole-cell voltage-clamp recording of Ih in the presence (gray) and absence (green) of 1 mM Cs+, an inhibitor of HCN channels. (F,G) Effects of complete replacement of bath Na+ with NMDG (F) and addition of tetrodotoxin (TTX) (G) on electrical activity in lactotrophs. (H) Effects of complete replacement of bath Na+ with NMDG on spontaneous Ca2+ signaling in lactotrophs. (I) Effects of complete replacement of bath Na+ with NMDG, choline chloride, and TMA on basal PRL release. (J) Schematic representation of effects of intracellular Ca2+ and cAMP on lactotroph function.

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