Somatostatin receptors

Abstract

In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing the characteristic seven-transmembrane-segment (STMS) topography. Years of intensive research have resulted in cloning of five receptor subtypes (sst(1)-sst(5)), one of which is represented by two splice variants (sst(2A) and sst(2B)). The individual subtypes, functionally coupled to the effectors of signal transduction, are differentially expressed throughout the mammalian organism, with corresponding differences in physiological impact. It is evident that receptor function, from a physiological point of view, cannot simply be reduced to the accumulated operations of individual receptors. Far from being isolated functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual receptor subtypes are highly cell-specific and vary with the co-expression of different-ligand receptors. However, the question is how to quantify the relative contributions of individual receptor subtypes to the integration of transduced signals, ultimately the result of collective receptor activity. The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype-sel...

Medical and surgical treatment options for polycystic liver disease1

“…47 This suggests that increased cAMP drives fluid secretion in hepatic cysts. Somatostatin analogs are cAMP level inhibitors and decrease fluid secretion and cell proliferation in many cell types, including cholangiocytes, 18,[48][49][50][51] thereby providing a novel opportunity to modulate cystogenesis. The basic concept is that cyst growth is regulated by a continuous process of secretion and reabsorption.…”

Synaptic transmission at retinal ribbon synapses

“…SRIF immunoreactivity is found in primarily in a subtype of amacrine cell. Its actions are mediated by several classes of G-protein-coupled receptors, labeled sst 1-5 (Moller et al, 2003). Although there is evidence that all classes of SRIF receptor are present in the vertebrate retina (Cristiani et al, 2002;Thermos, 2003), it is a splice variant of the sst 2 receptor, sst 2a which has been the focus of most physiological investigations of SRIF function.…”

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

“…The sst family comprises five G protein-coupled, seven-transmembrane domain receptors (sst1-5) widely distributed in normal and tumor tissues (Moller et al, 2003). Additionally, we recently identified two new truncated sst5 variants, sst5TMD5 and sst5TMD4, generated by non-canonical splicing, which are overexpressed in pituitary tumors (Duran-Prado et al, 2009), where they have a negative role, hindering the normal response of tumor cells to SST analogs (Dura´n-Prado et al, 2010).…”

“…Thus, ssts activation triggers inhibitory cascades by mechanisms dependent and independent of Gi/o proteins (Moller et al, 2003). This includes modulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK/1/2) and Akt phosphorylation (Moller et al, 2003), the two major signal transduction pathways involved in transformation, and enhanced proliferation and migration of cancer cells (Santen et al, 2002;Liu et al, 2007).…”

“…Thus, ssts activation triggers inhibitory cascades by mechanisms dependent and independent of Gi/o proteins (Moller et al, 2003). This includes modulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK/1/2) and Akt phosphorylation (Moller et al, 2003), the two major signal transduction pathways involved in transformation, and enhanced proliferation and migration of cancer cells (Santen et al, 2002;Liu et al, 2007). The antiproliferative effect of SST in breast cancer cells in vitro has long been known (Setyono-Han et al, 1987), and the particular role of sst2 has been further dissected recently by showing that it mediates an antiproliferative action in MCF-7 cells by inducing apoptosis and G1/S cell cycle arrest, and decreasing expression of epidermal growth factor receptor (He et al, 2009).…”