Somatostatin

Somatostatin binds to 5 subtypes of somatostatin receptors (SSTRs), which are all Gi-protein-coupled transmembrane receptors that inhibits adenylyl cyclase upon activation. By inhibiting intracellular cyclic AMP and Ca2+ and by a receptor-linked distal effect on exocytosis, SSTRs block cell secretion. The common pathway shared by the receptors involve the activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK). With the exception of SSTR3, activation of SSTRs lead to activation of voltage-gated potassium channels accompanied by increased K+ currents. This result in membrane hyperpolarization and inhibits depolarization-induced Ca2+ influx through voltage-sensitive Ca2+ channels. Depending on the receptor subtype, signalling cascades involve activation of other downstream targets such as Na+/H+ exchanger, Rho GTPase, and nitric oxide synthase (NOS). SSTRs 1 to 4 bind both somatostatin isoforms with equal nanomolar binding affinity whereas SSTR5 exhibits a 5- to 10-fold higher binding affinity for SST-28.

Effects of SSTR1: Upon biding of somatostatin and activation, SSTR1 mediates an antisecretory effect on growth hormone, prolactin and calcitonin.

Effects of SSTR2: SSTR2 subtype dominates in endocrine tissues. By binding to SST2 receptors, somatostatin exerts paracrine inhibitory actions on gastrin release from G cells, histamine release from ECL cells, and directly on parietal cell acid output. SSTR2 receptor signalling cascades also inhibit the secretion of growth hormone and that of adrenocorticotropin, glucagon, insulin, and interferon-γ.

Effects of SSTR3: Activation of these receptors lead to reduction in cell proliferation. SSTR3 triggers PTP-dependent cell apoptosis accompanied by activation of p53 and the pro-apoptotic protein Bax. A study of the matrigel sponge assay suggests that through SSTR3-mediated inhibition of both NOS and MAPK activities may lead to the antitumor effects of somatostatin in inhibiting tumor angiogenesis.

Effects of SSTR4: The functions of SSTR4 remain largely unknown.

Effects of SSTR5: Like SSTR2, SSTR5 subtype also predominates in endocrine tissues. Upon activation, SSTR5 signalling cascades exert an inhibitory action on growth hormone, adrenocorticotropin, insulin, and glucagon-like peptide-1 as well as the secretion of amylase.

The presence of somatostatin receptors has been identified in most neuroendocrine tumours, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas. The antitumor effects of somatostatin were also effective in various malignant lymphomas and breast tumours. Gastrointestinal hormones, such as gastrin, secretin, and cholecystokinin (CCK), as well as growth hormones and growth factors are thought to be elevated in gastrointestinal tract and neuroendocrine tumours and are inhibited by somatostatin. In vitro, somatostatin inhibited epidermal growth factor (EGF)-induced DNA synthesis and replication following which suggest that somatostatin may have direct anti-proliferative effects via SSTR signalling. Acromegaly is characterized as the endocrine disorder caused by a functioning tumour of cells that secrete growth hormone from the anterior pituitary. Somatostatin analogue therapies serve to normalize the elevated levels of GH and insulin-like growth factor 1 (IGF-1) and attenuate tumour growth.

In the vascular system this likely produces vasoconstriction by inhibiting adenylate cyclase leading to a lowering the concentration of cyclic adenosine monophosphate in the endothelial cells which ultimately blocks vasodilation through this pathway. This vasoconstriction is though the be responsible for reducing blood flow to the esophageal tissues and so reduces bleeding from esophageal varices.

Somatostatin mediates an analgesic activity by reducing vascular and nociceptive components of inflammation. Studies indicate that somatostatin may be present in nociceptive DRG neurons with C-fibers and primary afferent neurons to inhibit the release of transmitters at the presynaptic junctions of the sensory-efferent nerve terminals. Exogenous somatostatin has shown to inhibit the release of Substance P from central and peripheral nerve ending.