Regulator of G protein signaling Gb5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion

In pancreatic β 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 β cells remains largely unknown. R7 subfamily RGS proteins are stabilized by the G protein subunit Gb5, 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 Gβ5-RGS7 strongly promotes M3R-stimulated insulin secretion. Examination of this noncanonical mechanism in Gnb5^-/- MIN6 cells showed that cAMP, diacylglycerol, or Ca²⁺ levels were not significantly affected. There was no reduction in the amplitude of freeCa²⁺ responses in islets from the Gnb5^-/- mice, but the frequency of Ca²⁺ 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 Gb5-R7 in insulin secretion may lead to a new therapeutic approach for improving pancreatic b-cell function. - Wang, Q., Pronin, A.N.,Levay, K.,Almaca, J., Fornoni, A.,Caicedo, A., Slepak, V.Z. Regulator of G protein signaling Gβ5-R7 is a crucial activator of muscarinic M3 receptor-stimulated insulin secretion.