The role of M3-muscarinic receptor signaling in insulin secretion

Abstract

Recently, M3-muscarinic receptor (M3R) has been identified as the bona fide receptor responsible for the cholinergic regulation of glucose-induced insulin release. The molecular mechanisms of such regulation have also begun to be unravelled. These include the conventional G protein-dependent pathways involving calcium mobilization and activation of protein kinase C. In addition, recent studies also provided evidence for G protein-independent pathways in the regulation of insulin secretion by M3R. These include phosphorylation/arrestin-dependent activation of protein kinase D1, Src family kinase-dependent activation of the sodium channel NALCN and the involvement of regulator of G protein signalling (RGS)-4. Time has now come to extend these studies which were done mainly in rodents to human and explore the potential for targeting such pathways at different levels for the treatment of diseases with impaired insulin secretion such as type II diabetes.

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Figures and Tables

Figure 1 The possible mechanisms of M₃-muscarinic receptor (M3R)-mediated insulin secretion. Conventional studies have provided evidence that the transient, early phase of insulin secretion is mediated by M3R via G protein-dependent signaling that results in increase in intracellular calcium and activation of protein kinase C.1 Recent studies have shown that the sustained, late phase of insulin secretion is enhanced by M3R via G protein-independent pathways which requires receptor phosphorylation/arrestin-dependent signaling to PKD1 4 and Src family tyrosine kinases signaling to sodium channel NALCN.7

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