Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release.
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ABSTRACT: Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic ?-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)-G-protein coupling to G?(i/o) instead of G?(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 G?(i/o) rather than G?(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 G?(i/o) coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a-G?(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 ?-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.
SUBMITTER: Park S
PROVIDER: S-EPMC3503195 | biostudies-literature | 2012 Nov
REPOSITORIES: biostudies-literature
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