View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1616 (2003) 1–84 www.bba-direct.com Review Somatostatin receptors Lars Neisig Møllera, Carsten Enggaard Stidsenb, Bolette Hartmanna, Jens Juul Holsta,* a Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark b Novo Nordisk A/S, Bagsvaerd, Denmark Received 19 February 2003; received in revised form 16 July 2003; accepted 21 July 2003 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 (sst1-sst5), one of which is represented by two splice variants (sst2A and sst2B). 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. sst2 and sst5 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-selective analogues. Several have become available. D 2003 Elsevier B.V. All rights reserved. Keywords: Somatostatin receptor; Amino acid; Lipid; Carbohydrate 1. Introduction somatoliberin (somatotropin-releasing factor, SRF). But dur- ing the course of their investigations, they were compelled to In 1972, the search for releasing factors of the hypothal- revise the original working hypothesis, having recorded the amus was at its height, strongly encouraged by the recent consistently antisecretory response of somatotrophs to hypo- characterisation of neurosecretory peptides regulating the thalamic extracts, and it was instead the negative regulator of thyroid axis and reproduction. The existence of distinct pituitary somatotropin (growth hormone, GH) release that release-inhibiting factors, on the other hand, had still not was finally isolated from ovine hypothalami. It was named gained the acceptance of the scientific community at large, let somatostatin (somatotropin release-inhibiting factor, SRIF), alone been corroborated by anything but indirect evidence [1]. according to its hypophysiotropic actions, and eventually Brazeau et al. [2] for their part undertook to find the putative turned out to be a cyclic polypeptide with two biologically active isoforms: the tetradecapeptide SRIF-14 and the amino- * Corresponding author. Tel.: +45-3532-7518; fax: +45-3532-7537. terminally extended octacosapeptide SRIF-28. The heteroge- E-mail address: [email protected] (J.J. Holst). neity of the regulatory peptide derives from differential 0005-2736/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0005-2736(03)00235-9 2 L.N. Møller et al. / Biochimica et Biophysica Acta 1616 (2003) 1–84 posttranslational processing of a prepro-SRIF precursor of as epidermal growth factor (EGF) and somatomedin C/ 116 amino acids [3,4].1 The single human SRIF gene is insulin-like growth factor 1 (IGF-1) [59–63]. located on chromosome 3q28 [5,6]. Twenty-three years after the discovery of SRIF, de Lecea In the years to follow, a steady flow of reports disclosed et al. [64] could announce that they had cloned a rat the ubiquitous functions of SRIF. High-affinity, specific neuropeptide bearing strong resemblance to SRIF, at least SRIF receptors have been identified throughout the organ in purely structural terms. With a double reference to its systems of various mammals, sometimes with discrete distribution pattern in the CNS and neurodepressant actions, species variations in distribution and density. Structurally, this novel peptide transmitter was named cortistatin (CST). those receptors belong to the so-called ‘‘superfamily’’ of G A tetradecapeptide itself, corresponding to the highly con- protein-coupled (GPC) receptors. served carboxyl terminus of prepro-CST, the rodent homo- As for the physiological lineaments, SRIF is classically logue shares as many as 11 amino acids with SRIF [65,66]. known to inhibit the secretion of a wide range of hormones, Unlike SRIF, however, CST seems so far to be confined to including the pituitary GH [7–13], prolactin (PL) [9], and rather well-defined neuronal subpopulations of the CNS. As thyrotropin (thyroid-stimulating hormone, TSH) [9,14], vir- an invariant feature of its expression by inhibitory inter- tually every major hormone of the gastrointestinal tract neurones of the cerebral cortex and hippocampus, CST has (GIT), e.g. cholecystokinin (CCK), gastric inhibitory pep- been reported to show cellular colocalisation with gamma- tide (GIP), gastrin, motilin, neurotensin, and secretin [15– aminobutyric acid (GABA), both transmitters interfering 20], and glucagon, insulin, and pancreatic polypeptide (PP) with pyramidal cell firing [65,67,68]. In the hippocampal of the pancreatic islets of Langerhans (PIL) [21–24]. formation, however, CST is typically colocalised with SRIF Inhibition extends to the exocrine activity of salivary as well [66,69]. But transcription of CST and SRIF genes, as glands (amylase), gastrointestinal mucosa (hydrochloric it appears from comparison of upstream promoter regions, is acid, pepsinogen, intrinsic factor) [25,26], pancreatic acini subject to widely different regulation [66]. Although various (enzymes, bicarbonate) [16,20,26–29], and liver (bile) physiological parameters, including transitions between [26,29–31]. Similarly, intestinal absorption of key nutrients sleep phases [64,70,71], consolidation of short- and long- (glucose, fat, and amino acids) is inhibited by SRIF [32– term memory [67,68], and locomotor activity [71], respond 34]. But with regard to gastrointestinal motility, the phar- in a clearly transmitter-specific manner to SRIF and CST, macodynamic actions of SRIF are fairly complex, breaking the latter is nevertheless recognised to be an endogenous with simplistic notions of a universal inhibitor. While ligand at SRIF receptors, binding each subtype with an delaying the late phase of gastric emptying, weakening affinity in the nanomolar range. Evidence of special CST gallbladder contraction [26,30], and prolonging small-intes- receptors has never emerged [72–74].2 The prepro-CST tinal transit time, SRIF thus accelerates early gastric emp- gene maps to a region of the mouse chromosome 4 showing tying [35,36] and shortens the interval between migrating conserved synteny with human 1p36 [65].Thehuman motor complexes [37]. At the bottom line, however, a stable homologue of CST really seems to be a heptadecapeptide SRIF analogue such as octreotide (SMS 201–995) induces a (CST-17). It displays an arginine for lysine substitution, 3- to 4-fold increase in orocecal transit time [26,34,38]. compared to rat and mouse CST (CST-14), and it is amino- Mesenteric hemodynamics, similar to intestinal absorption terminally extended by three amino acids [65,75].By and motility, has also proved to be responsive to SRIF, with analogy with SRIF, there may also be a naturally occurring a drop in portal (and variceal)