SSTR2

Official Full Name

somatostatin receptor 2

Organism

Homo sapiens

GeneID

6752

Background

Somatostatin acts at many sites to inhibit the release of many hormones and other secretory proteins. The biologic effects of somatostatin are probably mediated by a family of G protein-coupled receptors that are expressed in a tissue-specific manner. SSTR2 is a member of the superfamily of receptors having seven transmembrane segments and is expressed in highest levels in cerebrum and kidney. [provided by RefSeq, Jul 2008]

Synonyms

SST2;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MDMADEPLNGSHTWLSIPFDLNGSVVSTNTSNQTEPYYDLTSNAVLTFIYFVVCIIGLCGNTLVIYVILRYAKMKTITNIYILNLAIADELFMLGLPFLAMQVALVHWPFGKAICRVVMTVDGINQFTSIFCLTVMSIDRYLAVVHPIKSAKWRRPRTAKMITMAVWGVSLLVILPIMIYAGLRSNQWGRSSCTINWPGESGAWYTGFIIYTFILGFLVPLTIICLCYLFIIIKVKSSGIRVGSSKRKKSEKKVTRMVSIVVAVFIFCWLPFYIFNVSSVSMAISPTPALKGMFDFVVVLTYANSCANPILYAFLSDNFKKSFQNVLCLVKVSGTDDGERSDSKQDKSRLNETTETQRTLLNGDLQTSI

Open

Disease

Alzheimer disease, Cushing syndrome, Diagnostic imaging, Endocrine gland neoplasm, Lung cancer, Pituitary gland disorder, Stomach cancer

Approved Drug

5 +

Clinical Trial Drug

5 +

Discontinued Drug

1 +

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Detailed Information

Somatostatin (SOM) is a neuropeptide widely distributed in the central nervous system and the whole body. It was first isolated and characterized based on its strong inhibitory effect on the secretion of pituitary hormones by endocrine cells from the anterior pituitary gland. Somatostatin receptors (SSTR) are 7 spanning trans-membrane G-protein-coupled receptors, which have multiple functions in both normal and tumor tissues. Somatostatin receptors are widely but variably expressed in normal tissue. They are diversely expressed in a variety of tumor types including a subset of prostate, pancreatic, breast, neuroendocrine and hepatocellular carcinomas. At present, five subtypes of SSTRs have been isolated; but research has focused on SSTR2, which is the best characterized member of the SSTR family. SSTR2 has many direct and indirect effects on cell cycling, apoptosis, angiogenesis, and growth factor signal transduction. It classically signals by inhibition of adenylate cyclase, inhibits calcium influx, increases p53 influx and mainly plays a role through downstream mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) and other downstream kinases.

SSTR2 and Tumors

SSTR2 mediates antitumour activity by blocking cell division and inducing apoptosis as well as inhibiting the secretion of growth factors or angiogenesis. Thus, in human meningioma, in vitro antiproliferative effects of SST and its analogues have been demonstrated. SSTR2 has been shown to be expressed in canine neuroendocrine tumours, including insulinoma and gastrinoma, as well as in adrenocortical and mammary tumours. After stimulation with an agonist and GRK2-mediated phosphorylation of its C-terminus, SSTR2 showed high affinity and co-internalize with β-arrestins. In central neurons, this can result in prolonged intracellular sequestration of the internalized receptor for up to 2 days before recycling to the cell surface in the dendritic compartment. This leads to profound desensitization to SOM. The long-term desensitization of SSTR2 following internalization has a pathophysiological relevance in epileptic hippocampus, which is characterized by SOMergic hyperinnervation. The cell surface density of SSTR2 is greatly reduced in both animal models and human epileptic hippocampus. Considering the inhibitory nature of SOM, this desensitization may well contribute to hyperexcitability of hippocampal neurons in status epilepticus. In contrast, no desensitization is observed in acromegaly patients, a condition due to GH hypersecretion, who are routinely treated with the SSTR2-preferring agonist for long periods of time.

Some studies have shown that SSTR2 is highly expressed in a variety of SCLC cell lines, as well as in small-cell lung carcinoma (SCLC) patient tumors and contributes to tumor progression. Notably, there was a strong correlation between SSTR2 expression and NEUROD1 expression in both cell lines and primary SCLC tumors. NEUROD1-predominant SCLC cell lines have been associated with variant pathology and NEUROD1 high mouse models are related to cMyc expression and a more aggressive phenotype. SSTR2 may contribute to this aggressive phenotype. Moreover, SSTR2 expression does not inhibit cancer cell survival in SCLC. In vivo and in vitro studies have shown decreased growth with loss of SSTR2 in multiple SCLC and related contexts. SSTR2 signaling supports cellular survival in SCLC and high-grade neuroendocrine carcinomas.

SSTR2 may also play an important role as a local inhibitor of FSH action on granulosa cells (GCs) apoptosis and steroidogenesis. It has been found that continuous i.c.v. infusion of Aβ25-35 induces a selective decrease in SSTR2 mRNA and protein levels in the frontal and temporal cortices of rat, suggesting that its alterations in human Alzheimer's disease (AD) brain, which may be pharmacological target candidates for prevention and treatment of AD.

References:

Si Y, et al. Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy. Cancer Gene Therapy, 2020: 1-14.
Alshafie W, et al. Characterization of agonist-dependent somatostatin receptor subtype 2 trafficking in neuroendocrine cells. Endocrine, 2020.
Foiani G, et al. Somatostatin receptor 2 expression in canine meningioma. Journal of comparative pathology, 2019, 166: 59-68.
Tan X, et al. SSTR2 associated with neuronal apoptosis after intracerebral hemorrhage in adult rats. Neurological research, 2018, 40(3): 221-230.
Lehman J M, et al. Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer. International journal of cancer, 2019, 144(5): 1104-1114.

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