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

Proc. Natl. Acad. Sci. U.S.A.2012 Nov 13;109(46):19003-8. Epub 2012 Oct 29
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摘要


Both ghrelin and somatostatin 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 receptor subtype 5 and that in the absence of ghrelin enhances GSIS. At concentrations of GHS-R1a and duanyu19425 expressed in islets, time-resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of heteromers in which ghrelin, but not suppresses GSIS and cAMP accumulation. GHS-R1a-G-protein coupling and the formation of GHS-R1a:duanyu19425 heteromers is dependent on the ratio of ghrelin to 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 ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet duanyu1942 concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than duanyu1942 establishes inhibitory tone on the β-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:duanyu19425 heteromerization that explains differential regulation of islet function by ghrelin and duanyu1942. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context.

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