The somatostatin (SST) receptor family controls pituitary hormone secretion, but the distribution and specific roles of these receptors on the excitability and voltage-gated calcium signaling of hormone producing pituitary cells have not been fully characterized. Here we show that the rat pituitary gland expressed Sstr1, Sstr2, Sstr3, and Sstr5 receptor genes in a cell type-specific manner: Sstr1 and Sstr2 in thyrotrophs, Sstr3 in gonadotrophs and lactotrophs, Sstr2, Sstr3, and Sstr5 in somatotrophs, and none in corticotrophs and melanotrophs. Most gonadotrophs and thyrotrophs spontaneously fired high-amplitude single action potentials, which were silenced by SST without affecting intracellular calcium concentrations. In contrast, lactotrophs and somatotrophs spontaneously fired low-amplitude plateau-bursting action potentials in conjunction with calcium transients, both of which were silenced by SST. Moreover, SST inhibited GPCR-induced voltage-gated calcium signaling and hormone secretion in all cell types expressing SST receptors, but the inhibition was more pronounced in somatotrophs. The pattern of inhibition of electrical activity and calcium signaling was consistent with both direct and indirect inhibition of voltage-gated calcium channels, the latter being driven by cell type-specific hyperpolarization. These results indicate that the action of SST in somatotrophs is enhanced by the expression of several types of SST receptors and their slow desensitization, that SST may play a role in the electrical resynchronization of gonadotrophs, thyrotrophs, and lactotrophs, and that the lack of SST receptors in corticotrophs and melanotrophs keeps them excitable and ready to responses to stress.

Department for Neurobiology Institute for Biological Research Sinisa Stankovic National Institute of Republic of Serbia University of Belgrade Belgrade Serbia

Laboratory of Biological Modeling National Institute of Diabetes Digestive and Kidney Diseases National Institutes of Health Bethesda USA

Laboratory of Pain Research Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Section on Cellular Signaling The Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda USA

See more in PubMed

Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J, A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins, Cell, 104 (2001) 849–859. PubMed

Pulichino AM, Vallette-Kasic S, Tsai JP, Couture C, Gauthier Y, Drouin J, Tpit determines alternate fates during pituitary cell differentiation, Genes Dev, 17 (2003) 738–747. PubMed PMC

Ingraham HA, Flynn SE, Voss JW, Albert VR, Kapiloff MS, Wilson L, Rosenfeld MG, The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions, Cell, 61 (1990) 1021–1033. PubMed

Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL, The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis, Genes Dev, 8 (1994) 2302–2312. PubMed

Stojilkovic SS, Tabak J, Bertram R, Ion channels and signaling in the pituitary gland, Endocr Rev, 31 (2010) 845–915. PubMed PMC

Van Goor F, Zivadinovic D, Martinez-Fuentes AJ, Stojilkovic SS, Dependence of pituitary hormone secretion on the pattern of spontaneous voltage-gated calcium influx. Cell type-specific action potential secretion coupling, J Biol Chem, 276 (2001) 33840–33846. PubMed

Fletcher PA, Sherman A, Stojilkovic SS, Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells, Mol Cell Endocrinol, 463 (2018) 23–36. PubMed PMC

Tsaneva-Atanasova K, Sherman A, van Goor F, Stojilkovic SS, Mechanism of spontaneous and receptor-controlled electrical activity in pituitary somatotrophs: experiments and theory, J Neurophysiol, 98 (2007) 131–144. PubMed

Zemkova H, Tomic M, Kucka M, Aguilera G, Stojilkovic SS, Spontaneous and CRH-Induced Excitability and Calcium Signaling in Mice Corticotrophs Involves Sodium, Calcium, and Cation-Conducting Channels, Endocrinology, 157 (2016) 1576–1589. PubMed PMC

Shipston MJ, Control of anterior pituitary cell excitability by calcium-activated potassium channels, Mol Cell Endocrinol, 463 (2018) 37–48. PubMed

Stojilkovic SS, Molecular mechanisms of pituitary endocrine cell calcium handling, Cell Calcium, 51 (2012) 212–221. PubMed PMC

Theodoropoulou M, Stalla GK, Somatostatin receptors: from signaling to clinical practice, Front Neuroendocrinol, 34 (2013) 228–252. PubMed

O’Carroll AM, Krempels K, Widespread distribution of somatostatin receptor messenger ribonucleic acids in rat pituitary, Endocrinology, 136 (1995) 5224–5227. PubMed

Epelbaum J, Briard N, Djordjijevic D, Dutour A, Meyerhoff W, Oliver C, Slama A, Viollet C, Zhang J, Characterization of somatostatin receptor subtypes in mammalian pituitary, Ann N Y Acad Sci, 839 (1998) 249–253. PubMed

Ben-Shlomo A, Melmed S, Pituitary somatostatin receptor signaling, Trends Endocrinol Metab, 21 (2010) 123–133. PubMed PMC

Day R, Dong W, Panetta R, Kraicer J, Greenwood MT, Patel YC, Expression of mRNA for somatostatin receptor (sstr) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis, Endocrinology, 136 (1995) 5232–5235. PubMed

Kumar U, Laird D, Srikant CB, Escher E, Patel YC, Expression of the five somatostatin receptor (SSTR1–5) subtypes in rat pituitary somatotrophes: quantitative analysis by double-layer immunofluorescence confocal microscopy, Endocrinology, 138 (1997) 4473–4476. PubMed

Mezey E, Hunyady B, Mitra S, Hayes E, Liu Q, Schaeffer J, Schonbrunn A, Cell specific expression of the sst2A and sst5 somatostatin receptors in the rat anterior pituitary, Endocrinology, 139 (1998) 414–419. PubMed

Ocampo Daza D, Sundstrom G, Bergqvist CA, Larhammar D, The evolution of vertebrate somatostatin receptors and their gene regions involves extensive chromosomal rearrangements, BMC Evol Biol, 12 (2012) 231. PubMed PMC

Yang SK, Parkington HC, Epelbaum J, Keating DJ, Chen C, Somatostatin decreases voltage-gated Ca2+ currents in GH3 cells through activation of somatostatin receptor 2, Am J Physiol Endocrinol Metab, 292 (2007) E1863–1870. PubMed

Ben-Shlomo A, Liu NA, Melmed S, Somatostatin and dopamine receptor regulation of pituitary somatotroph adenomas, Pituitary, 20 (2017) 93–99. PubMed

Holl RW, Thorner MO, Leong DA, Intracellular calcium concentration and growth hormone secretion in individual somatotropes: effects of growth hormone-releasing factor and somatostatin, Endocrinology, 122 (1988) 2927–2932. PubMed

Rawlings SR, Hoyland J, Mason WT, Calcium homeostasis in bovine somatotrophs: calcium oscillations and calcium regulation by growth hormone-releasing hormone and somatostatin, Cell Calcium, 12 (1991) 403–414. PubMed

Fukata J, Diamond DJ, Martin JB, Effects of rat growth hormone (rGH)-releasing factor and somatostatin on the release and synthesis of rGH in dispersed pituitary cells, Endocrinology, 117 (1985) 457–467. PubMed

Nussinovitch I, Somatostatin inhibits two types of voltage-activated calcium currents in rat growth-hormone secreting cells, Brain Res, 504 (1989) 136–138. PubMed

Sims SM, Lussier BT, Kraicer J, Somatostatin activates an inwardly rectifying K+ conductance in freshly dispersed rat somatotrophs, J Physiol, 441 (1991) 615–637. PubMed PMC

Drouin J, De Lean A, Rainville D, Lachance R, Labrie F, Characteristics of the interaction between thyrotropin-releasing hormone and somatostatin for thyrotropin and prolactin release, Endocrinology, 98 (1976) 514–521. PubMed

Epelbaum J, Enjalbert A, Krantic S, Musset F, Bertrand P, Rasolonjanahary R, Shu C, Kordon C, Somatostatin receptors on pituitary somatotrophs, thyrotrophs, and lactotrophs: pharmacological evidence for loose coupling to adenylate cyclase, Endocrinology, 121 (1987) 2177–2185. PubMed

Eigler T, Ben-Shlomo A, Somatostatin system: molecular mechanisms regulating anterior pituitary hormones, J Mol Endocrinol, 53 (2014) R1–19. PubMed

Kraicer J, Gajewski TC, Moor BC, Release of pro-opiomelanocortin-derived peptides from the pars intermedia and pars distalis of the rat pituitary: effect of corticotrophin-releasing factor and somatostatin, Neuroendocrinology, 41 (1985) 363–373. PubMed

Yu WH, Kimura M, McCann SM, Effect of somatostatin on the release of gonadotropins in male rats, Proc Soc Exp Biol Med, 214 (1997) 83–86. PubMed

Janjic MM, Previde RM, Fletcher PA, Sherman A, Smiljanic K, Abebe D, Bjelobaba I, Stojilkovic SS, Divergent expression patterns of pituitary gonadotropin subunit and GnRH receptor genes to continuous GnRH in vitro and in vivo, Sci Rep, 9 (2019) 20098. PubMed PMC

Fletcher PA, Smiljanic K, Previde RM, Constantin S, Sherman AS, Coon SL, Stojilkovic SS, The astroglial and stem cell functions of adult rat folliculostellate cells, Glia, 71 (2023) 205–228. PubMed PMC

Stojilkovic SS, Bjelobaba I, Zemkova H, Ion Channels of Pituitary Gonadotrophs and Their Roles in Signaling and Secretion, Front Endocrinol (Lausanne), 8 (2017) 126. PubMed PMC

Login IS, Judd AM, MacLeod RM, Association of 45Ca2+ mobilization with stimulation of growth hormone (GH) release by GH-releasing factor in dispersed normal male rat pituitary cells, Endocrinology, 118 (1986) 239–243. PubMed

Lussier BT, Wood DA, French MB, Moor BC, Kraicer J, Free intracellular Ca2+ concentration ([Ca2+]i) and growth hormone release from purified rat somatotrophs. II. Somatostatin lowers [Ca2+]i by inhibiting Ca2+ influx, Endocrinology, 128 (1991) 583–591. PubMed

Petrucci C, Cervia D, Buzzi M, Biondi C, Bagnoli P, Somatostatin-induced control of cytosolic free calcium in pituitary tumour cells, Br J Pharmacol, 129 (2000) 471–484. PubMed PMC

Cervia D, Petrucci C, Bluet-Pajot MT, Epelbaum J, Bagnoli P, Inhibitory control of growth hormone secretion by somatostatin in rat pituitary GC cells: sst(2) but not sst(1) receptors are coupled to inhibition of single-cell intracellular free calcium concentrations, Neuroendocrinology, 76 (2002) 99–110. PubMed

Ishibashi M, Yamaji T, Mechanism of the inhibitory action of dopamine and somatostatin on prolactin secretion from human lactotrophs in culture, J Clin Endocrinol Metab, 60 (1985) 599–606. PubMed

Lussier BT, French MB, Moor BC, Kraicer J, Free intracellular Ca2+ concentration and growth hormone (GH) release from purified rat somatotrophs. III. Mechanism of action of GH-releasing factor and somatostatin, Endocrinology, 128 (1991) 592–603. PubMed

Lussier BT, French MB, Moore BC, Kraicer J, Free intracellular Ca2+ concentration ([Ca2+]i) and growth hormone release from purified rat somatotrophs. I. GH-releasing factor-induced Ca2+ influx raises [Ca2+]i, Endocrinology, 128 (1991) 570–582. PubMed

Naumov AP, Herrington J, Hille B, Actions of growth-hormone-releasing hormone on rat pituitary cells: intracellular calcium and ionic currents, Pflugers Arch, 427 (1994) 414–421. PubMed

Kwiecien R, Tseeb V, Kurchikov A, Kordon C, Hammond C, Growth hormone-releasing hormone triggers pacemaker activity and persistent Ca2+ oscillations in rat somatotrophs, J Physiol, 499 (Pt 3) (1997) 613–623. PubMed PMC

Tomic M, Koshimizu T, Yuan D, Andric SA, Zivadinovic D, Stojilkovic SS, Characterization of a plasma membrane calcium oscillator in rat pituitary somatotrophs, J Biol Chem, 274 (1999) 35693–35702. PubMed

Cuttler L, Glaum SR, Collins BA, Miller RJ, Calcium signalling in single growth hormone-releasing factor-responsive pituitary cells, Endocrinology, 130 (1992) 945–953. PubMed

Persani L, Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity, Thyroid, 8 (1998) 941–946. PubMed

Hinkle PM, Gehret AU, Jones BW, Desensitization, trafficking, and resensitization of the pituitary thyrotropin-releasing hormone receptor, Front Neurosci, 6 (2012) 180. PubMed PMC

Freeman ME, Kanyicska B, Lerant A, Nagy G, Prolactin: structure, function, and regulation of secretion, Physiol Rev, 80 (2000) 1523–1631. PubMed

Mollard P, Vacher P, Dufy B, Barker JL, Somatostatin blocks Ca2+ action potential activity in prolactin-secreting pituitary tumor cells through coordinate actions on K+ and Ca2+ conductances, Endocrinology, 123 (1988) 721–732. PubMed

Chen C, Zhang J, Vincent JD, Israel JM, Two types of voltage-dependent calcium current in rat somatotrophs are reduced by somatostatin, J Physiol, 425 (1990) 29–42. PubMed PMC

Scherubl H, Hescheler J, Riecken EO, Molecular mechanisms of somatostatin’s inhibition of hormone release: participation of voltage-gated calcium channels and G-proteins, Horm Metab Res Suppl, 27 (1993) 1–4. PubMed

Yamashita N, Shibuya N, Ogata E, Hyperpolarization of the membrane potential caused by somatostatin in dissociated human pituitary adenoma cells that secrete growth hormone, Proc Natl Acad Sci U S A, 83 (1986) 6198–6202. PubMed PMC

Tallent M, Liapakis G, O’Carroll AM, Lolait SJ, Dichter M, Reisine T, Somatostatin receptor subtypes SSTR2 and SSTR5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20, Neuroscience, 71 (1996) 1073–1081. PubMed

Kato M, Withdrawal of somatostatin augments L-type Ca2+ current in primary cultured rat somatotrophs, J Neuroendocrinol, 7 (1995) 855–859. PubMed

Chen ZP, Xu S, Lightman SL, Hall L, Levy A, Intracellular calcium ion responses to somatostatin in cells from human somatotroph adenomas, Clin Endocrinol (Oxf), 46 (1997) 45–53. PubMed

Lewis DL, Weight FF, Luini A, A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line, Proc Natl Acad Sci U S A, 83 (1986) 9035–9039. PubMed PMC

Reisine T, Bell GI, Molecular biology of somatostatin receptors, Endocr Rev, 16 (1995) 427–442. PubMed

Kleuss C, Somatostatin modulates voltage-dependent Ca2+ channels in GH3 cells via a specific G(o) splice variant, Ciba Found Symp, 190 (1995) 171–182; discussion 182–176. PubMed

Chen C, Clarke IJ, G(o)-2 protein mediates the reduction in Ca2+ currents by somatostatin in cultured ovine somatotrophs, J Physiol, 491 (Pt 1) (1996) 21–29. PubMed PMC

Chen C, Gi-3 protein mediates the increase in voltage-gated K+ currents by somatostatin on cultured ovine somatotrophs, Am J Physiol, 275 (1998) E278–284. PubMed

Vale W, Rivier C, Brazeau P, Guillemin R, Effects of somatostatin on the secretion of thyrotropin and prolactin, Endocrinology, 95 (1974) 968–977. PubMed

Shimon I, Yan X, Taylor JE, Weiss MH, Culler MD, Melmed S, Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors, J Clin Invest, 100 (1997) 2386–2392. PubMed PMC

Lee SC, Shin SH, Somatostatin does not inhibit prolactin synthesis in normal male rat pituitary cells but inhibits prolactin synthesis in estradiol-primed pituitary cells, J Endocrinol, 148 (1996) 69–76. PubMed

Goth MI, Lyons CE Jr., Ellwood MR, Barrett JR, Thorner MO, Chronic estrogen treatment in male rats reveals mammosomatotropes and allows inhibition of prolactin secretion by somatostatin, Endocrinology, 137 (1996) 274–280. PubMed

Schussler N, Farnoud R, Rauch C, Roche M, Berthet M, Thomas F, Peillon F, Bayet MC, Effect of the slow-release formulation of somatuline (BIM 23014) on estrogen-induced hyperprolactinemia and lactotroph hyperplasia in the female rat, Neuropeptides, 26 (1994) 399–404. PubMed

Meyerhof W, The elucidation of somatostatin receptor functions: a current view, Rev Physiol Biochem Pharmacol, 133 (1998) 55–108. PubMed

Viollet C, Bodenant C, Prunotto C, Roosterman D, Schaefer J, Meyerhof W, Epelbaum J, Vaudry H, Leroux P, Differential expression of multiple somatostatin receptors in the rat cerebellum during development, J Neurochem, 68 (1997) 2263–2272. PubMed