title: Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release.
abstract: 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.
authors.affiliation: Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL 33458, USA.
authors.forename: Seongjoon
authors.initials: S
authors.lastname: Park
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhang
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D055503:Protein Multimerization / Q000502:physiology*; D051381:Rats; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism
chemical_list: D054439:Ghrelin; D007328:Insulin; D054440:Receptors, Ghrelin; D017481:Receptors, Somatostatin; D013004:Somatostatin; C094573:somatostatin receptor 5; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11