title: Critical metabolic roles of β-cell M3 muscarinic acetylcholine receptors.
abstract: Muscarinic acetylcholine (ACh) receptors (mAChRs; M(1)-M(5)) regulate the activity of an extraordinarily large number of important physiological processes. We and others previously demonstrated that pancreatic β-cells are endowed with M(3) mAChRs which are linked to G proteins of the G(q) family. The activation of these receptors by ACh or other muscarinic agonists leads to the augmentation of glucose-induced insulin release via multiple mechanisms. Interestingly, in humans, ACh acting on human β-cell mAChRs is released from adjacent α-cells which express both choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (vAChT), indicative of the presence of a non-neuronal cholinergic system in human pancreatic islets. In order to shed light on the physiological roles of β-cell M(3) receptors, we recently generated and analyzed various mutant mouse models. Specifically, we carried out studies with mice which overexpressed M(3) receptors or mutant M(3) receptors in pancreatic β-cells or which selectively lacked M(3) receptors or M(3)-receptor-associated proteins in pancreatic β-cells. Our findings indicate that β-cell M(3) receptors play a key role in maintaining proper insulin release and whole body glucose homeostasis and that strategies aimed at enhancing signaling through β-cell M(3) receptors may prove useful to improve β-cell function for the treatment of type 2 diabetes (T2D).
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
authors.forename: Inigo
authors.initials: I
authors.lastname: Ruiz de Azua
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gautam
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D020710:RGS Proteins / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D020710:RGS Proteins; D043587:Receptor, Muscarinic M3; C098799:RGS4 protein; D005947:Glucose