Navarro F, Malagon MM, Luque RM, Castaño JP. Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominantnegative modulators for sst2-mediated signaling. Am J Physiol Endocrinol Metab 303: E1325-E1334, 2012. First published October 2, 2012; doi:10.1152/ajpendo.00445.2012.-Somatostatin (SST) and its related peptide cortistatin (CORT) exert their multiple actions through binding to the SST receptor (sst) family, generally considered to comprise five G protein-coupled receptors with seven transmembrane domains (TMD), named sst1-sst5, plus a splice sst2B variant. However, we recently discovered that human and rodent sst5 gene expression also generates, through noncanonical alternative splicing, novel truncated albeit functional sst5 variants with less than seven TMD. Here, we cloned and characterized for the first time the porcine wild-type sst5 (psst5, full-length) and identified two novel truncated psst5 variants with six and three TMD, thus termed psst5TMD6 and psst5TMD3, respectively. In line with that observed in human and rodent truncated sst5 variants, psst5TMD6 and psst5TMD3 are functional (e.g., activate calcium signaling), selectively respond to SST and CORT, respectively, and exhibit specific tissue expression profiles that differ from full-length psst5 and often overlaps with psst2 expression. Moreover, fluorescence resonance energy transfer analysis shows that psst5 truncated variants physically interact with psst2, thereby altering their localization at the plasma membrane and specifically disrupting the cellular response to SST and/or CORT. These results represent the first characterization of a key porcine SST receptor, psst5, and, together with our previous results, provide strong evidence that alternative splicing-derived, truncated sst5 variants with distinct functional capacities exist in the mammalian lineage, where they can act as dominant-negative receptors, by interacting directly with long, seven TMD variants, potentially contributing to modulate normal and pathological SST and CORT signaling. somatostatin; cortistatin; somatostatin receptor; truncated receptor; dominant-negative receptor SOMATOSTATIN (SST) is a neuropeptide that exerts its multiple actions, including inhibition of neuroendocrine secretions, neurotransmission, and regulation of gastrointestinal functions, through a family of receptors (sst) belonging to the superfamily of G protein-coupled receptors (GPCR) with seven transmembrane domains (TMDs) (24,27). In mammals, the sst family comprises five distinct receptors (sst1-5) encoded by different, nonallelic, and intronless genes (24,27,28,38) and, in some species, an alternatively COOH-terminal spliced isoform of the sst2, the sst2B, originated by processing of a cryptic intron located in the 3=-untranslated region (UTR) (28, 36). These receptors also mediate the effects of cortistatin (CORT), a peptide that shows a remarkable sequential and structural homology with SST (10). In fact, SST and CORT share many actions, especially their ability to regulate the...
The majority of the biological actions attributed to somatostatin (SST) are thought to be mediated by SST receptor 2 (sst2), the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in (patho)physiological situations (i.e., endometriosis, type 2 diabetes). Moreover, sst1 together with sst2 and sst5 is involved in the well-known actions of SST on pituitary somatotropes in pig and primates. Here, we cloned the porcine sst1 (psst1) and performed a structural and functional characterization using both primary and heterologous models. The psst1 sequence presents the majority of signature motifs shared among G proteincoupled receptors and, specifically, among ssts and exhibits a high homology with other mammalian sst1, with only minor differences in the amino-terminal domain, reinforcing the idea of an early evolutive divergence between mammalian and nonmammalian sst1s. psst1 is functional in terms of decreasing cAMP levels in response to SST when transfected in heterologous models. The psst1 receptor is expressed in several tissues, and analyses of gene cis elements predict regulation by multiple transcription factors and metabolic stimuli. Finally, psst1 is coexpressed with other sst subtypes in various tissues, and in vitro data demonstrate that psst1 can interact with itself forming homodimers and with other ssts forming heterodimers. These data highlight the functional importance of sst1 on the SST-mediated effects and its functional interaction with different ssts, which point out the necessity of exploring the consequences of such interactions. somatostatin receptor 1, promoter regulation; expression profile; heterodimerization; fluorescence resonance energy transfer; adenosine 3=,5=-cyclic monophosphate SOMATOSTATIN (SST) is a peptide hormone mainly produced by neuroendocrine cells (18,50). It was first isolated from the ovine hypothalamus (6), and soon thereafter isolated and sequenced in porcine hypothalami (45). SST acts as an endogenous inhibitory regulator of various cellular functions, including hormone secretion, motility, and proliferation (5,11,26,32,36,40). SST has two active forms (14 and 28 amino acids) with comparable subnanomolar affinity for a family of G protein-coupled receptors (GPCRs) widely distributed in the brain and periphery and named SST receptors (ssts) (34, 36). To date, five separate sst genes have been described (sst1-sst5), encoding six to nine different isoforms, depending on the species (10,14,16,36). Although more than one sst subtype can be simultaneously expressed in certain cell types, the expression pattern and levels depend on the tissue, the age, and the physiological status (11,29,36).The majority of biological actions associated with SST are thought to be mediated by sst2, the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in physiological and pathophysiological situations. I...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.