First Author | Wang Q | Year | 2017 |
Journal | FASEB J | Volume | 31 |
Issue | 11 | Pages | 4734-4744 |
PubMed ID | 28687610 | Mgi Jnum | J:253323 |
Mgi Id | MGI:6108545 | Doi | 10.1096/fj.201700197RR |
Citation | Wang Q, et al. (2017) Regulator of G-protein signaling Gbeta5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion. FASEB J 31(11):4734-4744 |
abstractText | In pancreatic beta cells, muscarinic cholinergic receptor M3 (M3R) stimulates glucose-induced secretion of insulin. Regulator of G-protein signaling (RGS) proteins are critical modulators of GPCR activity, yet their role in beta cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G-protein subunit Gbeta5, such that the knockout of the Gnb5 gene results in degradation of all R7 subunits. We found that Gnb5 knockout in mice or in the insulin-secreting MIN6 cell line almost completely eliminates insulinotropic activity of M3R. Moreover, overexpression of Gbeta5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5(-/-) MIN6 cells showed that cAMP, diacylglycerol, or Ca(2+) levels were not significantly affected. There was no reduction in the amplitude of free Ca(2+) responses in islets from the Gnb5(-/-) mice, but the frequency of Ca(2+) oscillations induced by cholinergic agonist was lowered by more than 30%. Ablation of Gnb5 impaired M3R-stimulated phosphorylation of ERK1/2. Stimulation of the ERK pathway in Gnb5(-/-) cells by epidermal growth factor restored M3R-stimulated insulin release to near normal levels. Identification of the novel role of Gbeta5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic beta-cell function.-Wang, Q., Pronin, A. N., Levay, K., Almaca, J., Fornoni, A., Caicedo, A., Slepak, V. Z. Regulator of G-protein signaling Gbeta5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion. |