| First Author | Park S | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 46 | Pages | 19003-8 |
| PubMed ID | 23112170 | Mgi Jnum | J:191736 |
| Mgi Id | MGI:5462492 | Doi | 10.1073/pnas.1209590109 |
| Citation | Park S, et al. (2012) Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. Proc Natl Acad Sci U S A 109(46):19003-8 |
| abstractText | Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)-G-protein coupling to Galpha(i/o) instead of Galpha(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 Galpha(i/o) rather than Galpha(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 Galpha(i/o) coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a-Galpha(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 beta-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. |
