Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release

• DOI: 10.1073/pnas.1209590109
• Publication Date: 2012-10-30T05:46:22Z
• Authors: Seongjoon Park; Hong Jiang; Hongjie Zhang; Roy G. Smith
• Keywords: 0303 health sciences; GTP-Binding Protein alpha Subunits, Gi-Go; Ghrelin; Rats; Mice; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Insulin-Secreting Cells; Insulin Secretion; Animals; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Insulin; Receptors, Somatostatin; Protein Multimerization; Receptors, Ghrelin; Somatostatin; Signal Transduction

Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)–G-protein coupling to Gα i/o instead of Gα q11 and dependence on energy balance. Here we present evidence for an equilibrium model of receptor heteromerization that fulfills these criteria. We show that GHS-R1a coupling to Gα i/o rather than Gα q11 requires interactions between GHS-R1a and SST receptor subtype 5 (SST5) and that in the absence of SST5 ghrelin enhances GSIS. At concentrations of GHS-R1a and SST5 expressed in islets, time-resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, suppresses GSIS and cAMP accumulation. GHS-R1a–G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghrelin to SST. A high ratio enhances heteromer formation and Gα i/o coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a–Gα q11 coupling. The [ghrelin]/[SST] ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet SST concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than SST establishes inhibitory tone on the β-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential regulation of islet function by ghrelin and SST. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context.