Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 15;99(4):789–798. doi: 10.1172/JCI119225

Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation.

I Shimon 1, J E Taylor 1, J Z Dong 1, R A Bitonte 1, S Kim 1, B Morgan 1, D H Coy 1, M D Culler 1, S Melmed 1
PMCID: PMC507864  PMID: 9045884

Abstract

Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.

Full Text

The Full Text of this article is available as a PDF (287.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ackland J., Ratter S., Bourne G. L., Rees L. H. Characterisation of immunoreactive somatostatin in human fetal hypothalamic tissue. Regul Pept. 1983 Jan;5(2):95–101. doi: 10.1016/0167-0115(83)90117-9. [DOI] [PubMed] [Google Scholar]
  2. Akita S., Webster J., Ren S. G., Takino H., Said J., Zand O., Melmed S. Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J Clin Invest. 1995 Mar;95(3):1288–1298. doi: 10.1172/JCI117779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asa S. L., Kovacs K., Horvath E., Losinski N. E., Laszlo F. A., Domokos I., Halliday W. C. Human fetal adenohypophysis. Electron microscopic and ultrastructural immunocytochemical analysis. Neuroendocrinology. 1988 Oct;48(4):423–431. doi: 10.1159/000125044. [DOI] [PubMed] [Google Scholar]
  4. Asa S. L., Kovacs K., Singer W. Human fetal adenohypophysis: morphologic and functional analysis in vitro. Neuroendocrinology. 1991 Jun;53(6):562–572. doi: 10.1159/000125775. [DOI] [PubMed] [Google Scholar]
  5. Bertherat J., Brue T., Enjalbert A., Gunz G., Rasolonjanahary R., Warnet A., Jaquet P., Epelbaum J. Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effects of octreotide upon in vivo and in vitro hormonal secretions. J Clin Endocrinol Metab. 1992 Aug;75(2):540–546. doi: 10.1210/jcem.75.2.1353505. [DOI] [PubMed] [Google Scholar]
  6. Breder C. D., Yamada Y., Yasuda K., Seino S., Saper C. B., Bell G. I. Differential expression of somatostatin receptor subtypes in brain. J Neurosci. 1992 Oct;12(10):3920–3934. doi: 10.1523/JNEUROSCI.12-10-03920.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bruno J. F., Xu Y., Song J., Berelowitz M. Molecular cloning and functional expression of a brain-specific somatostatin receptor. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11151–11155. doi: 10.1073/pnas.89.23.11151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Cohen C. B., Jonsen A. R. The future of the fetal tissue bank. The National Advisory Board on Ethics in Reproduction. Science. 1993 Dec 10;262(5140):1663–1665. doi: 10.1126/science.8259510. [DOI] [PubMed] [Google Scholar]
  10. Coy D. H., Taylor J. E. Receptor-specific somatostatin analogs: correlations with biological activity. Metabolism. 1996 Aug;45(8 Suppl 1):21–23. doi: 10.1016/s0026-0495(96)90073-6. [DOI] [PubMed] [Google Scholar]
  11. Day R., Dong W., Panetta R., Kraicer J., Greenwood M. T., Patel Y. C. Expression of mRNA for somatostatin receptor (sstr) types 2 and 5 in individual rat pituitary cells. A double labeling in situ hybridization analysis. Endocrinology. 1995 Nov;136(11):5232–5235. doi: 10.1210/endo.136.11.7588263. [DOI] [PubMed] [Google Scholar]
  12. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  13. DeNoto F. M., Moore D. D., Goodman H. M. Human growth hormone DNA sequence and mRNA structure: possible alternative splicing. Nucleic Acids Res. 1981 Aug 11;9(15):3719–3730. doi: 10.1093/nar/9.15.3719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fukata J., Diamond D. J., Martin J. B. Effects of rat growth hormone (rGH)-releasing factor and somatostatin on the release and synthesis of rGH in dispersed pituitary cells. Endocrinology. 1985 Aug;117(2):457–467. doi: 10.1210/endo-117-2-457. [DOI] [PubMed] [Google Scholar]
  15. Goodyer C. G., Branchaud C. L., Lefebvre Y. Effects of growth hormone (GH)-releasing factor and somatostatin on GH secretion from early to midgestation human fetal pituitaries. J Clin Endocrinol Metab. 1993 May;76(5):1259–1264. doi: 10.1210/jcem.76.5.8098715. [DOI] [PubMed] [Google Scholar]
  16. Goodyer C. G., Marcovitz S., Hardy J., Lefebvre Y., Guyda H. J., Posner B. I. Effect of insulin-like growth factors on human foetal, adult normal and tumour pituitary function in tissue culture. Acta Endocrinol (Copenh) 1986 May;112(1):49–57. doi: 10.1530/acta.0.1120049. [DOI] [PubMed] [Google Scholar]
  17. Greenman Y., Melmed S. Expression of three somatostatin receptor subtypes in pituitary adenomas: evidence for preferential SSTR5 expression in the mammosomatotroph lineage. J Clin Endocrinol Metab. 1994 Sep;79(3):724–729. doi: 10.1210/jcem.79.3.7521350. [DOI] [PubMed] [Google Scholar]
  18. Greenman Y., Melmed S. Heterogeneous expression of two somatostatin receptor subtypes in pituitary tumors. J Clin Endocrinol Metab. 1994 Feb;78(2):398–403. doi: 10.1210/jcem.78.2.8106629. [DOI] [PubMed] [Google Scholar]
  19. Hashimoto K., Koga M., Motomura T., Kasayama S., Kouhara H., Ohnishi T., Arita N., Hayakawa T., Sato B., Kishimoto T. Identification of alternatively spliced messenger ribonucleic acid encoding truncated growth hormone-releasing hormone receptor in human pituitary adenomas. J Clin Endocrinol Metab. 1995 Oct;80(10):2933–2939. doi: 10.1210/jcem.80.10.7559877. [DOI] [PubMed] [Google Scholar]
  20. Hoyer D., Bell G. I., Berelowitz M., Epelbaum J., Feniuk W., Humphrey P. P., O'Carroll A. M., Patel Y. C., Schonbrunn A., Taylor J. E. Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci. 1995 Mar;16(3):86–88. doi: 10.1016/s0165-6147(00)88988-9. [DOI] [PubMed] [Google Scholar]
  21. Kacsóh B., Tóth B. E., Avery L. M., Grosvenor C. E. In vitro control of prolactin (PRL) and growth hormone secretion of neonatal rat pituitary glands: effects of ovine PRL, salmon calcitonin, endothelin-3, angiotensin II, bromocryptine and somatostatin. Life Sci. 1993;52(3):259–269. doi: 10.1016/0024-3205(93)90217-q. [DOI] [PubMed] [Google Scholar]
  22. Katznelson L., Oppenheim D. S., Coughlin J. F., Kliman B., Schoenfeld D. A., Klibanski A. Chronic somatostatin analog administration in patients with alpha-subunit-secreting pituitary tumors. J Clin Endocrinol Metab. 1992 Nov;75(5):1318–1325. doi: 10.1210/jcem.75.5.1358910. [DOI] [PubMed] [Google Scholar]
  23. Kaupmann K., Bruns C., Hoyer D., Seuwen K., Lübbert H. Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. FEBS Lett. 1993 Sep 27;331(1-2):53–59. doi: 10.1016/0014-5793(93)80296-7. [DOI] [PubMed] [Google Scholar]
  24. Klibanski A., Alexander J. M., Bikkal H. A., Hsu D. W., Swearingen B., Zervas N. T. Somatostatin regulation of glycoprotein hormone and free subunit secretion in clinically nonfunctioning and somatotroph adenomas in vitro. J Clin Endocrinol Metab. 1991 Dec;73(6):1248–1255. doi: 10.1210/jcem-73-6-1248. [DOI] [PubMed] [Google Scholar]
  25. Kubota A., Yamada Y., Kagimoto S., Shimatsu A., Imamura M., Tsuda K., Imura H., Seino S., Seino Y. Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. J Clin Invest. 1994 Mar;93(3):1321–1325. doi: 10.1172/JCI117090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lamberts S. W., Krenning E. P., Reubi J. C. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev. 1991 Nov;12(4):450–482. doi: 10.1210/edrv-12-4-450. [DOI] [PubMed] [Google Scholar]
  27. Lamberts S. W. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev. 1988 Nov;9(4):417–436. doi: 10.1210/edrv-9-4-417. [DOI] [PubMed] [Google Scholar]
  28. Law S. F., Yasuda K., Bell G. I., Reisine T. Gi alpha 3 and G(o) alpha selectively associate with the cloned somatostatin receptor subtype SSTR2. J Biol Chem. 1993 May 25;268(15):10721–10727. [PubMed] [Google Scholar]
  29. Lee S. C., Shin S. H. Somatostatin does not inhibit prolactin synthesis in normal male rat pituitary cells but inhibits prolactin synthesis in estradiol-primed pituitary cells. J Endocrinol. 1996 Jan;148(1):69–76. doi: 10.1677/joe.0.1480069. [DOI] [PubMed] [Google Scholar]
  30. Mandarino L., Stenner D., Blanchard W., Nissen S., Gerich J., Ling N., Brazeau P., Bohlen P., Esch F., Guillemin R. Selective effects of somatostatin-14, -25 and -28 on in vitro insulin and glucagon secretion. Nature. 1981 May 7;291(5810):76–77. doi: 10.1038/291076a0. [DOI] [PubMed] [Google Scholar]
  31. Miller G. M., Alexander J. M., Bikkal H. A., Katznelson L., Zervas N. T., Klibanski A. Somatostatin receptor subtype gene expression in pituitary adenomas. J Clin Endocrinol Metab. 1995 Apr;80(4):1386–1392. doi: 10.1210/jcem.80.4.7714115. [DOI] [PubMed] [Google Scholar]
  32. Moldovan S., Atiya A., Adrian T. E., Kleinman R. M., Lloyd K., Olthoff K., Imagawa D., Shevlin L., Coy D., Walsh J. Somatostatin inhibits B-cell secretion via a subtype-2 somatostatin receptor in the isolated perfused human pancreas. J Surg Res. 1995 Jul;59(1):85–90. doi: 10.1006/jsre.1995.1136. [DOI] [PubMed] [Google Scholar]
  33. Moreau J. P., Kim S., Dong J. Z., Ignatious F., Jackson S., Moreau S. C., Morgan B. A., Touraud F., Taylor J. E., Tissier B. Improved analogs and novel delivery systems for somatostatin octapeptides. Metabolism. 1996 Aug;45(8 Suppl 1):24–26. doi: 10.1016/s0026-0495(96)90074-8. [DOI] [PubMed] [Google Scholar]
  34. Morel G., Leroux P., Pelletier G. Ultrastructural autoradiographic localization of somatostatin-28 in the rat pituitary gland. Endocrinology. 1985 Apr;116(4):1615–1620. doi: 10.1210/endo-116-4-1615. [DOI] [PubMed] [Google Scholar]
  35. O'Carroll A. M., Krempels K. Widespread distribution of somatostatin receptor messenger ribonucleic acids in rat pituitary. Endocrinology. 1995 Nov;136(11):5224–5227. doi: 10.1210/endo.136.11.7588261. [DOI] [PubMed] [Google Scholar]
  36. O'Carroll A. M., Raynor K., Lolait S. J., Reisine T. Characterization of cloned human somatostatin receptor SSTR5. Mol Pharmacol. 1994 Aug;46(2):291–298. [PubMed] [Google Scholar]
  37. Panetta R., Patel Y. C. Expression of mRNA for all five human somatostatin receptors (hSSTR1-5) in pituitary tumors. Life Sci. 1995;56(5):333–342. doi: 10.1016/0024-3205(94)00956-2. [DOI] [PubMed] [Google Scholar]
  38. Patel Y. C., Greenwood M., Kent G., Panetta R., Srikant C. B. Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation. Biochem Biophys Res Commun. 1993 Apr 15;192(1):288–294. doi: 10.1006/bbrc.1993.1412. [DOI] [PubMed] [Google Scholar]
  39. Patel Y. C., Srikant C. B. Subtype selectivity of peptide analogs for all five cloned human somatostatin receptors (hsstr 1-5). Endocrinology. 1994 Dec;135(6):2814–2817. doi: 10.1210/endo.135.6.7988476. [DOI] [PubMed] [Google Scholar]
  40. RINNE U. K. NEUROSECRETORY MATERIAL PASSING INTO THE HYPOPHYSIAL PORTAL SYSTEM IN THE HUMAN INFUNDIBULUM, AND ITS FOETAL DEVELOPMENT. Acta Neuroveg (Wien) 1963 Jul 22;25:310–324. doi: 10.1007/BF01231988. [DOI] [PubMed] [Google Scholar]
  41. Raynor K., Murphy W. A., Coy D. H., Taylor J. E., Moreau J. P., Yasuda K., Bell G. I., Reisine T. Cloned somatostatin receptors: identification of subtype-selective peptides and demonstration of high affinity binding of linear peptides. Mol Pharmacol. 1993 Jun;43(6):838–844. [PubMed] [Google Scholar]
  42. Raynor K., O'Carroll A. M., Kong H., Yasuda K., Mahan L. C., Bell G. I., Reisine T. Characterization of cloned somatostatin receptors SSTR4 and SSTR5. Mol Pharmacol. 1993 Aug;44(2):385–392. [PubMed] [Google Scholar]
  43. Reichlin S. Somatostatin. N Engl J Med. 1983 Dec 15;309(24):1495–1501. doi: 10.1056/NEJM198312153092406. [DOI] [PubMed] [Google Scholar]
  44. Reisine T., Bell G. I. Molecular biology of somatostatin receptors. Endocr Rev. 1995 Aug;16(4):427–442. doi: 10.1210/edrv-16-4-427. [DOI] [PubMed] [Google Scholar]
  45. Rens-Domiano S., Law S. F., Yamada Y., Seino S., Bell G. I., Reisine T. Pharmacological properties of two cloned somatostatin receptors. Mol Pharmacol. 1992 Jul;42(1):28–34. [PubMed] [Google Scholar]
  46. Reubi J. C., Landolt A. M. High density of somatostatin receptors in pituitary tumors from acromegalic patients. J Clin Endocrinol Metab. 1984 Dec;59(6):1148–1151. doi: 10.1210/jcem-59-6-1148. [DOI] [PubMed] [Google Scholar]
  47. Reubi J. C., Landolt A. M. The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab. 1989 Apr;68(4):844–850. doi: 10.1210/jcem-68-4-844. [DOI] [PubMed] [Google Scholar]
  48. Ridgway E. C., Klibanski A., Martorana M. A., Milbury P., Kieffer J. D., Chin W. W. The effect of somatostatin on the release of thyrotropin and its subunits from bovine anterior pituitary cells in vitro. Endocrinology. 1983 Jun;112(6):1937–1942. doi: 10.1210/endo-112-6-1937. [DOI] [PubMed] [Google Scholar]
  49. Rohrer L., Raulf F., Bruns C., Buettner R., Hofstaedter F., Schüle R. Cloning and characterization of a fourth human somatostatin receptor. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4196–4200. doi: 10.1073/pnas.90.9.4196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Samuels M. H., Henry P., Ridgway E. C. Effects of dopamine and somatostatin on pulsatile pituitary glycoprotein secretion. J Clin Endocrinol Metab. 1992 Jan;74(1):217–222. doi: 10.1210/jcem.74.1.1345783. [DOI] [PubMed] [Google Scholar]
  51. Schettini G. Brain somatostatin: receptor-coupled transducing mechanisms and role in cognitive functions. Pharmacol Res. 1991 Apr;23(3):203–215. doi: 10.1016/s1043-6618(05)80080-5. [DOI] [PubMed] [Google Scholar]
  52. Ullrich A., Gray A., Tam A. W., Yang-Feng T., Tsubokawa M., Collins C., Henzel W., Le Bon T., Kathuria S., Chen E. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J. 1986 Oct;5(10):2503–2512. doi: 10.1002/j.1460-2075.1986.tb04528.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Webb C. B., Thominet J. L., Frohman L. A. Ectopic growth hormone releasing factor stimulates growth hormone release from human somatotroph adenomas in vitro. J Clin Endocrinol Metab. 1983 Feb;56(2):417–419. doi: 10.1210/jcem-56-2-417. [DOI] [PubMed] [Google Scholar]
  54. Williams T. C., Kelijman M., Crelin W. C., Downs T. R., Frohman L. A. Differential effects of somatostatin (SRIH) and a SRIH analog, SMS 201-995, on the secretion of growth hormone and thyroid-stimulating hormone in man. J Clin Endocrinol Metab. 1988 Jan;66(1):39–45. doi: 10.1210/jcem-66-1-39. [DOI] [PubMed] [Google Scholar]
  55. Xu Y., Song J., Bruno J. F., Berelowitz M. Molecular cloning and sequencing of a human somatostatin receptor, hSSTR4. Biochem Biophys Res Commun. 1993 Jun 15;193(2):648–652. doi: 10.1006/bbrc.1993.1673. [DOI] [PubMed] [Google Scholar]
  56. Yamada Y., Kagimoto S., Kubota A., Yasuda K., Masuda K., Someya Y., Ihara Y., Li Q., Imura H., Seino S. Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype. Biochem Biophys Res Commun. 1993 Sep 15;195(2):844–852. doi: 10.1006/bbrc.1993.2122. [DOI] [PubMed] [Google Scholar]
  57. Yamada Y., Post S. R., Wang K., Tager H. S., Bell G. I., Seino S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):251–255. doi: 10.1073/pnas.89.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Yamada Y., Reisine T., Law S. F., Ihara Y., Kubota A., Kagimoto S., Seino M., Seino Y., Bell G. I., Seino S. Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. Mol Endocrinol. 1992 Dec;6(12):2136–2142. doi: 10.1210/mend.6.12.1337145. [DOI] [PubMed] [Google Scholar]
  59. Yamashita S., Melmed S. Insulinlike growth factor I regulation of growth hormone gene transcription in primary rat pituitary cells. J Clin Invest. 1987 Feb;79(2):449–452. doi: 10.1172/JCI112832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yasuda K., Rens-Domiano S., Breder C. D., Law S. F., Saper C. B., Reisine T., Bell G. I. Cloning of a novel somatostatin receptor, SSTR3, coupled to adenylylcyclase. J Biol Chem. 1992 Oct 5;267(28):20422–20428. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES