Porcine sst1 can physically interact with other somatostatin receptors, and its expression is regulated by metabolic/inflammatory sensors

Abstract

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...

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

“…Presence of binding sites for tissue-specific transcriptional factors of the POU domain protein family ( Rosenfeld, 1991 ) was also noted, including sites for pituitary-specific positive transcription factor 1 and POU family transcription factor Tst-1 that regulate tissue-specific rat Sstr1 gene expression in the pituitary and in pancreatic β -cells, respectively ( Baumeister and Meyerhof, 1998 , 2000b ). The porcine Sstr1 gene promoter showed positive regulation by cAMP (through a CREBBP1 binding site) ( Gahete et al, 2014 ), consistent with the cAMP-mediated upregulation of SST 1 mRNA in rat pituitary primary cultures induced by GHRH treatment ( Park et al, 2000 ), and in pituitary adenomas expressing a mutated G α s (gsp oncogene) that constitutively activates the cAMP pathway ( Kim et al, 2005 ). SST 1 mouse pituitary expression may also be controlled by testosterone because pituitary SST 1 mRNA levels are decreased in gonadectomized males but restored upon testosterone injection, and are increased by testosterone treatment in rat pituitary tumor cells (GH4C1 cells) ( Xu et al, 1995a ; Senaris et al, 1996 ).…”

“…Upregulation depends on phosphorylation events at the SST 1 C-terminal tail ( Hukovic et al, 1999 ). SST 1 immunoreactivity is observed both at the membrane and in the cytoplasm in primary and heterologous cell models ( Gahete et al, 2014 ), and in paraffin-embedded sections of diverse human tumor tissues, in contrast to SST 2 , which is predominantly membrane-associated ( Hofland et al, 1999 ; Lupp et al, 2013 ).…”

Targeting of Somatostatin Receptors Using Fluorescent Nanoparticles

“…These cells are target cells for that ligand while cells which do not have such a receptor cannot be influenced directly by that ligand [12]. There are five different SSTRs subtypes (SSTR1-5) since they are expressed at various sites in the body and distributed in different organs [13][14][15]. SSTRs are also expressed on blood cells [16][17][18][19][20][21][22].…”