Subtypes of the Somatostatin Receptor Assemble as Functional Homo- and Heterodimers

Abstract

The existence of receptor dimers has been proposed for several G protein-coupled receptors. However, the question of whether G protein-coupled receptor dimers are necessary for activating or modulating normal receptor function is unclear. We address this question with somatostatin receptors (SSTRs) of which there are five distinct subtypes. By using transfected mutant and wild type receptors, as well as endogenous receptors, we provide pharmacological, biochemical, and physical evidence, based on fluorescence resonance energy transfer analysis, that activation by ligand induces SSTR dimerization, both homo-and heterodimerization with other members of the SSTR family, and that dimerization alters the functional properties of the receptor such as ligand binding affinity and agonist-induced receptor internalization and up-regulation. Double label confocal fluorescence microscopy showed that when SSTR1 and SSTR5 subtypes were coexpressed in Chinese hamster ovary-K1 cells and treated with agonist they underwent internalization and were colocalized in cytoplasmic vesicles. SSTR5 formed heterodimers with SSTR1 but not with SSTR4 suggesting that heterodimerization is a specific process that is restricted to some but not all receptor subtype combinations. Direct protein interaction between different members of the SSTR subfamily defines a new level of molecular cross-talk between subtypes of the SSTR and possibly related receptor families.

A potential role of somatostatin and its receptor SSTR4 in the migration of hepatic oval cells

“…45 Increased expression of SSTRs 1, 2, and 5 were observed in this study (Figure 5a). Hence, it is possible that the dimerization of SSTR4 with another SSTR isotype may affect migration or other responses of HOCs.…”

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

“…Since we have demonstrated that inhibition of α 2B -AR cell-surface expression is mediated through dimerization of mutant and WT receptors, it is possible that the inhibitory effect of α 2B -ARm on the transport of α 2A -AR and α 2C -AR is also due to heterodimerization of α 2B -ARm with α 2A -AR or α 2C -AR. This possibility is supported by a number of observations demonstrating that closely related members of G protein-coupled receptors may heterodimerize [11,14,[37][38][39]. Furthermore, α 2A -AR and α 2C -AR indeed form heterodimers with β 1 -AR and M 3 -muscarinc receptor, respectively [40,41].…”

“…Therefore, dimers are unable to export from the ER. Dimerization has been well described for a variety of G protein-coupled receptors [9][10][11][12][13][14][15][34][35][36][37][38][39][40][41]. However, whether α 2B -AR is capable of forming homodimers has not been reported.…”

“…Whereas some G protein-coupled receptor dimers are constitutively formed in the ER and then transported to the cell surface, other receptors are assembled as dimers at the cell surface in an agonist-dependent fashion [38,39]. The α 2B -ARm, an ER-export deficient mutant, formed homodimers as well as heterodimers with α 2B -AR and trapped α 2B -AR in the ER.…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…Using cell-based expression studies it has been previously demonstrated that SSTR1 and SSTR5 exist as monomers in the basal state. However, in the presence of SST agonists, SSTR1 and SSTR5 are able to form heterodimers with each other (Rocheville et al, 2000;Patel et al, 2002). Since M a n u s c r i p t 12 both B-and A-cells of the endocrine express multiple SSTRs.…”