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Gene Review

SSTR2  -  somatostatin receptor 2

Homo sapiens

Synonyms: SRIF-1, SS-2-R, SS2-R, SS2R, Somatostatin receptor type 2
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Disease relevance of SSTR2


Psychiatry related information on SSTR2


High impact information on SSTR2

  • The neuropeptide somatostatin (SRIF) has diverse physiological actions in the brain and endocrine organs [10].
  • The availability of the cloned receptors will now allow for detailed structure-function analysis of SRIF receptors and will facilitate development of subtype-selective agonists and antagonists that could be useful in the treatment of central nervous system and endocrine disorders [10].
  • Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified [11].
  • Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4) [11].
  • Four of the subtypes (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis [11].

Chemical compound and disease context of SSTR2


Biological context of SSTR2

  • There is 46% identity and 70% similarity between the amino acid sequences of SSTR1 and SSTR2 [17].
  • Whereas growth inhibition has been reported to follow stimulation of protein tyrosine phosphatase via SSTR2 or inhibition of Ca2+ channels via SSTR5 in heterologous expression systems, the subtype selectivity for signaling apoptosis has not been investigated [18].
  • On the other hand, in the nonresponder group, CT secretion was reduced by the SSTR1 selective agonist, whereas cell viability was inhibited by SSTR2 selective agonists [19].
  • No association between SSTR2 genotypes and GH and IGF-I levels was found [20].
  • The present study demonstrates that the human MTC cell line TT stably expresses all the SSTR subtypes and responds to SSTR2 and SSTR5 activation by subtype-selective agonists with two different patterns in terms of [(3)H]thymidine ([(3)H]thy) incorporation and cell number [21].

Anatomical context of SSTR2

  • RNA blotting studies show that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively [17].
  • We expressed two somatostatin receptor subtypes, SSTR1 and SSTR2, stably in mouse fibroblast Ltk- cells and transiently in human embryonic kidney HEK293 cells to investigate subtype-specific pharmacological and functional properties [12].
  • We found that the previously identified SSTR1 and SSTR2 are the major subtypes expressed in this cell line [22].
  • Cultured tumor cells were treated with SRIH, lanreotide (BIM-23014), or SRIH analogs selective for SSTR2 (BIM-23120), SSTR5 (BIM-23206), or SSTR1 (BIM-23926) [23].
  • SSTR1 and SSTR2 immunoreactivity (-ir) was observed on a variety of cells within all analyzed tissues including cornea, iris, trabecular meshwork, Schlemm's canal, ciliary processes, ciliary muscle, retina, choroid, cultured RPE cells, and optic nerve [24].

Associations of SSTR2 with chemical compounds

  • We have also found that human SSTR2 shows a high affinity for SMS 201-995, which has been used clinically for the treatment of endocrine tumors [1].
  • Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs [25].
  • The expression of SSTR2 and/or SSTR5 was 100%, consistent with the presence of RC-160 binding [26].
  • In contrast, the SSTR2 receptor was insensitive to CGP 23996-like compounds but bound MK 678 with high affinity [13].
  • SSTR2-infected tumors were visible on imaging 6 days after VV injection and could be visualized for up to 3 weeks post-viral injection using repeat injections of 111In-pentetreotide [27].
  • A combined treatment of a demethylating agent, 5-aza-2-deoxycytidine and a histone deacetylase inhibitor, trichostatin A, leads to increased expression of hSSTR2 mRNA in cell lines in which the CpG island is methylated [28].

Physical interactions of SSTR2

  • SRIF2 receptors are not efficiently coupled to G proteins and have a distinct but overlapping distribution in brain with SRIF1 receptors [5].
  • In contrast, SSTR5 bound very few SRIF analogues with high affinity [29].
  • Membranes from a cell line exhibiting highest expression of SSTR2 gene bound SS and its analogue, octreotide, with moderate affinity [30].
  • However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05) [25].
  • These results indicate that human SSTR2 is functionally coupled to Gi alpha 1 protein but not to Gi alpha 2 or Gi alpha 3 when expressed in CHO cells [31].
  • Given that SST analogs show preferential binding to SSTR2, these data provide a mechanism for their effectiveness in controlling pituitary tumors and the absence of tolerance seen in patients undergoing long-term administration [32].

Regulatory relationships of SSTR2

  • SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms [25].
  • Nevertheless, SRIF stimulated AC even in the presence of forskolin at higher doses of SRIF in PTX-treated hSSTR5-expressing cells [33].
  • Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53 [34].
  • However, somatostatin-14 inhibits the adenylyl cyclase in a dose dependent and pertussis toxin-sensitive manner when human SSTR2 is co-expressed with Gi alpha 1 in CHO cells [31].
  • In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability [35].

Other interactions of SSTR2

  • 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 [25].
  • The subtype SSTR1 was expressed alone in 4 cases, SSTR2 was expressed alone in 33 cases, and SSTR3 was expressed alone in one case [3].
  • Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors [36].
  • Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005) [2].
  • Moreover, SHP-1 associates with SSTR2 depending on its activation [37].

Analytical, diagnostic and therapeutic context of SSTR2


  1. Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analogue SMS 201-995 in treatment of human endocrine tumors. Kubota, A., Yamada, Y., Kagimoto, S., Shimatsu, A., Imamura, M., Tsuda, K., Imura, H., Seino, S., Seino, Y. J. Clin. Invest. (1994) [Pubmed]
  2. 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. Shimon, I., Yan, X., Taylor, J.E., Weiss, M.H., Culler, M.D., Melmed, S. J. Clin. Invest. (1997) [Pubmed]
  3. Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors using in situ hybridization. Reubi, J.C., Schaer, J.C., Waser, B., Mengod, G. Cancer Res. (1994) [Pubmed]
  4. Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238. Plonowski, A., Schally, A.V., Nagy, A., Sun, B., Szepeshazi, K. Cancer Res. (1999) [Pubmed]
  5. Somatostatin receptors. Raynor, K., Reisine, T. Critical reviews in neurobiology. (1992) [Pubmed]
  6. Somatostatin impairs sleep in elderly human subjects. Frieboes, R.M., Murck, H., Schier, T., Holsboer, F., Steiger, A. Neuropsychopharmacology (1997) [Pubmed]
  7. Somatostatin receptors in brain and pituitary. Epelbaum, J., Agid, F., Agid, Y., Beaudet, A., Bertrand, P., Enjalbert, A., Heidet, V., Kordon, C., Krantic, S., Léonard, J.F. Horm. Res. (1989) [Pubmed]
  8. The neurobiology of somatostatin. Epelbaum, J., Dournaud, P., Fodor, M., Viollet, C. Critical reviews in neurobiology. (1994) [Pubmed]
  9. CSF somatostatin in anorexia nervosa and bulimia: relationship to the hypothalamic pituitary-adrenal cortical axis. Kaye, W.H., Rubinow, D., Gwirtsman, H.E., George, D.T., Jimerson, D.C., Gold, P.W. Psychoneuroendocrinology (1988) [Pubmed]
  10. Molecular biology of somatostatin receptors. Bell, G.I., Reisine, T. Trends Neurosci. (1993) [Pubmed]
  11. Somatostatin and its receptor family. Patel, Y.C. Frontiers in neuroendocrinology. (1999) [Pubmed]
  12. Subtype-specific signaling mechanisms of somatostatin receptors SSTR1 and SSTR2. Hou, C., Gilbert, R.L., Barber, D.L. J. Biol. Chem. (1994) [Pubmed]
  13. Pharmacological properties of two cloned somatostatin receptors. Rens-Domiano, S., Law, S.F., Yamada, Y., Seino, S., Bell, G.I., Reisine, T. Mol. Pharmacol. (1992) [Pubmed]
  14. Expression of somatostatin receptor subtypes 2 and 4 in human benign prostatic hyperplasia and prostatic cancer. Hansson, J., Bjartell, A., Gadaleanu, V., Dizeyi, N., Abrahamsson, P.A. Prostate (2002) [Pubmed]
  15. Somatostatin receptor-specific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors. Danila, D.C., Haidar, J.N., Zhang, X., Katznelson, L., Culler, M.D., Klibanski, A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  16. Somatostatin receptor subtype expression and function in human vascular tissue. Curtis, S.B., Hewitt, J., Yakubovitz, S., Anzarut, A., Hsiang, Y.N., Buchan, A.M. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  17. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Yamada, Y., Post, S.R., Wang, K., Tager, H.S., Bell, G.I., Seino, S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  18. Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Sharma, K., Patel, Y.C., Srikant, C.B. Mol. Endocrinol. (1996) [Pubmed]
  19. Selective activation of somatostatin receptor subtypes differentially modulates secretion and viability in human medullary thyroid carcinoma primary cultures: potential clinical perspectives. Zatelli, M.C., Piccin, D., Tagliati, F., Bottoni, A., Luchin, A., Vignali, C., Margutti, A., Bondanelli, M., Pansini, G.C., Pelizzo, M.R., Culler, M.D., Degli Uberti, E.C. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  20. Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly. Filopanti, M., Ronchi, C., Ballarè, E., Bondioni, S., Lania, A.G., Losa, M., Gelmini, S., Peri, A., Orlando, C., Beck-Peccoz, P., Spada, A. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  21. Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt. Zatelli, M.C., Tagliati, F., Taylor, J.E., Rossi, R., Culler, M.D., degli Uberti, E.C. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  22. Pituitary cell line GH3 expresses two somatostatin receptor subtypes that inhibit adenylyl cyclase: functional expression of rat somatostatin receptor subtypes 1 and 2 in human embryonic kidney 293 cells. Garcia, P.D., Myers, R.M. Mol. Pharmacol. (1994) [Pubmed]
  23. Somatostatin analogs in vitro effects in a growth hormone-releasing hormone-secreting bronchial carcinoid. Zatelli, M.C., Maffei, P., Piccin, D., Martini, C., Rea, F., Rubello, D., Margutti, A., Culler, M.D., Sicolo, N., degli Uberti, E.C. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  24. Somatostatin receptor gene expression in human ocular tissues: RT-PCR and immunohistochemical study. Klisovic, D.D., O'Dorisio, M.S., Katz, S.E., Sall, J.W., Balster, D., O'Dorisio, T.M., Craig, E., Lubow, M. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  25. Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. Shimon, I., Taylor, J.E., Dong, J.Z., Bitonte, R.A., Kim, S., Morgan, B., Coy, D.H., Culler, M.D., Melmed, S. J. Clin. Invest. (1997) [Pubmed]
  26. High expression of somatostatin receptors and messenger ribonucleic acid for its receptor subtypes in organ-confined and locally advanced human prostate cancers. Halmos, G., Schally, A.V., Sun, B., Davis, R., Bostwick, D.G., Plonowski, A. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  27. Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using 111In-pentetreotide. McCart, J.A., Mehta, N., Scollard, D., Reilly, R.M., Carrasquillo, J.A., Tang, N., Deng, H., Miller, M., Xu, H., Libutti, S.K., Alexander, H.R., Bartlett, D.L. Mol. Ther. (2004) [Pubmed]
  28. Identification of an upstream promoter of the human somatostatin receptor, hSSTR2, which is controlled by epigenetic modifications. Torrisani, J., Hanoun, N., Laurell, H., Lopez, F., Maoret, J.J., Souque, A., Susini, C., Cordelier, P., Buscail, L. Endocrinology (2008) [Pubmed]
  29. Characterization of cloned somatostatin receptors SSTR4 and SSTR5. Raynor, K., O'Carroll, A.M., Kong, H., Yasuda, K., Mahan, L.C., Bell, G.I., Reisine, T. Mol. Pharmacol. (1993) [Pubmed]
  30. Gene expression of somatostatin receptor subtypes, SSTR1 and SSTR2, in human lung cancer cell lines. Fujita, T., Yamaji, Y., Sato, M., Murao, K., Takahara, J. Life Sci. (1994) [Pubmed]
  31. Human somatostatin receptor, SSTR2, is coupled to adenylyl cyclase in the presence of Gi alpha 1 protein. Kagimoto, S., Yamada, Y., Kubota, A., Someya, Y., Ihara, Y., Yasuda, K., Kozasa, T., Imura, H., Seino, S., Seino, Y. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  32. Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization. Grant, M., Alturaihi, H., Jaquet, P., Collier, B., Kumar, U. Mol. Endocrinol. (2008) [Pubmed]
  33. Phospholipase C activation and Ca2+ mobilization by cloned human somatostatin receptor subtypes 1-5, in transfected COS-7 cells. Akbar, M., Okajima, F., Tomura, H., Majid, M.A., Yamada, Y., Seino, S., Kondo, Y. FEBS Lett. (1994) [Pubmed]
  34. Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. Teijeiro, R., Rios, R., Costoya, J.A., Castro, R., Bello, J.L., Devesa, J., Arce, V.M. Cell. Physiol. Biochem. (2002) [Pubmed]
  35. Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Zatelli, M.C., Piccin, D., Vignali, C., Tagliati, F., Ambrosio, M.R., Bondanelli, M., Cimino, V., Bianchi, A., Schmid, H.A., Scanarini, M., Pontecorvi, A., De Marinis, L., Maira, G., Uberti, E.C. Endocr. Relat. Cancer (2007) [Pubmed]
  36. Somatostatin receptor subtype gene expression in pituitary adenomas. Miller, G.M., Alexander, J.M., Bikkal, H.A., Katznelson, L., Zervas, N.T., Klibanski, A. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  37. SRC homology-2-containing protein tyrosine phosphatase-1 restrains cell proliferation in human medullary thyroid carcinoma. Zatelli, M.C., Piccin, D., Tagliati, F., Bottoni, A., Luchin, A., degli Uberti, E.C. Endocrinology (2005) [Pubmed]
  38. Two amino acids, located in transmembrane domains VI and VII, determine the selectivity of the peptide agonist SMS 201-995 for the SSTR2 somatostatin receptor. Kaupmann, K., Bruns, C., Raulf, F., Weber, H.P., Mattes, H., Lübbert, H. EMBO J. (1995) [Pubmed]
  39. Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. Jaquet, P., Saveanu, A., Gunz, G., Fina, F., Zamora, A.J., Grino, M., Culler, M.D., Moreau, J.P., Enjalbert, A., Ouafik, L.H. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  40. Different expression patterns of somatostatin receptor subtypes in cultured epithelial cells from human normal prostate and prostate cancer. Sinisi, A.A., Bellastella, A., Prezioso, D., Nicchio, M.R., Lotti, T., Salvatore, M., Pasquali, D. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
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