Somatostatin and its receptor family

Somatostatin (SST), a regulatory peptide, is produced by neuroendocrine, in flammatory, and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors, and cytok ines. The peptide is released in large amounts from storage pools of secret ory cells, or in small amounts from activated immune and inflammatory cells , and acts as an endogenous inhibitory regulator of the secretory and proli ferative responses of target cells that are widely distributed in the brain and periphery. These actions are mediated by a family of seven transmembra ne (TM) domain G-protein-coupled receptors that comprise five distinct subt ypes (termed SSTR1-5) that are endoded by separate genes segregated on diff erent chromosomes. The five receptor subtypes bind the natural SST peptides , SST-14 and SST-28; with low nanomolar affinity. Short synthetic octapepti de and hexapeptide analogs bind well to only three of the subtypes, 2, 3, a nd 5. Selective nonpeptide agonists with nanomolar affinity have been devel oped for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide ant agonists for SSTR2 and SSTR5 have been identified. The ligand binding domai n for SST ligands is made up of residues in TMs III-VII with a potential co ntribution by the second extracellular loop. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell . The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dep endent mechanisms. Some of the subtypes are also coupled to inward rectifyi ng K+ channels (SSTR2, 3, 4, 5), to voltage-dependent Ca2+ channels (SSTR1, 2), a Na+/H+ exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2) , phospholipase C (SSTR2, 5); and phospholipase A(2) (SSTR4). SSTRs block c ell secretion by inhibiting intracellular cAMP and Ca2+ and by a receptor-l inked distal effect on exocytosis. Four of the receptors (SSTR1, 2, 4, and 5) induce cell cycle arrest via PTP-dependent modulation of MAPK, associate d with induction of the retinoblastoma tumor suppressor protein and p21. In contrast, SSTR3 uniquely triggers PTP-dependent apoptosis accompanied by a ctivation of p53 and the pro-apoptotic protein Bar. SSTR1, 2, 3, and 5 disp lay acute desensitization of adenylyl cyclase coupling. Four of the subtype s (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis. SSTR1 f ails to be internalized but is instead upregulated at the membrane in respo nse to continued agonist exposure. Among the wide spectrum of SST effects, several biological responses have been identified that display absolute or relative subtype selectivity. These include GH secretion (SSTR2 and 5), ins ulin secretion (SSTR5), glucagon secretion (SSTR2), and immune responses (S STR2).