Gβ5‐R7 regulator of G protein signaling complex is a positive regulator of insulin secretion

Abstract

We present new data describing the function of the atypical G protein beta subunit Gβ5 (gene: Gnb5). Gβ5 is unique in that instead of Gγ dimerizes with regulator of G protein signaling proteins of R7 family (RGS6, 7, 9 and 11). These obligatory protein complexes are known to be highly expressed in neurons, but have also been found in other tissues, for example in endocrine glands. Here, we show that Gβ5‐R7 plays a novel and surprisingly important role in stimulated insulin exocytosis. We demonstrated earlier that CRISPR/Cas9‐mediated deletion of the Gnb5 gene ininsulin‐secreting cell line MIN6 results in a dramatic reduction insulin secretion induced by muscarinic M3 receptor (M3R). Our data on the knockout of Gnb5 in mice also results in about 2‐fold lower level of serum insulin, and in a dramatic reduction in M3R‐stimulated secretion occurs in Gnb5−/− primary islets. These results are unexpected because in other systems, the knockout of this RGS protein complex facilitates signal transduction, apparently to its GAP activity toward Gi family proteins. In this study, we show that deletion of Gβ5‐R7 strongly attenuates inputs from different secretagogues, not only M3R. The knockout of the Gnb5 gene affects Gq‐ and Gs‐mediated stimulation, but most surprisingly, there is a significant effect on glucose, the permissive factor for insulin release. The Gnb5 knockout does not impair second messengers cAMP, Ca2+and DAG in beta cells, but rather causes changes protein phosphorylation pattern. Our experiments also implicate regulation of some protein kinases including ERKs and ROCK and participation of cell‐to‐cell interaction mechanisms, possibly adhesion GPCRs. Thus, our experiments point to the existence of a novel function of the Gβ5‐R7 complex that may be not directly associated with its interaction with heterotrimeric G proteins.Support or Funding InformationThis work was supported by U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grants R01DK105427 (to V.Z.S.) and R01DK111538 (to Alejandro Caicedo). The authors declare no conflicts of interest.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.