The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice
Open Access
- 1 June 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (6), 2184-2193
- https://doi.org/10.1172/jci41541
Abstract
A variety of neurotransmitters, gastrointestinal hormones, and metabolic signals are known to potentiate insulin secretion through GPCRs. We show here that β cell–specific inactivation of the genes encoding the G protein α-subunits Gαq and Gα11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gαq/Gα11-deficient β cells were not restricted to loss of muscarinic or metabolic potentiation of insulin release; the response to glucose per se was also diminished. Electrophysiological recordings revealed that glucose-induced depolarization of isolated β cells was impaired in the absence of Gαq/Gα11, and closure of KATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of β cell–autonomous potentiation of insulin secretion through factors cosecreted with insulin. We identified as autocrine mediators involved in this process extracellular nucleotides such as uridine diphosphate acting through the Gq/G11-coupled P2Y6 receptor and extracellular calcium acting through the calcium-sensing receptor. Thus, the Gq/G11-mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators.This publication has 90 references indexed in Scilit:
- CCK activates RhoA and Rac1 differentially through Gα13and Gαqin mouse pancreatic aciniAmerican Journal of Physiology-Cell Physiology, 2010
- Deletion of GPR40 Impairs Glucose-Induced Insulin Secretion In Vivo in Mice Without Affecting Intracellular Fuel Metabolism in IsletsDiabetes, 2009
- Anatomical Profiling of G Protein-Coupled Receptor ExpressionCell, 2008
- Thrombin‐promoted release of UDP‐glucose from human astrocytoma cellsBritish Journal of Pharmacology, 2008
- β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetesProceedings of the National Academy of Sciences of the United States of America, 2007
- Probing cell type–specific functions of Gi in vivo identifies GPCR regulators of insulin secretionJCI Insight, 2007
- Ca2+‐dependent ATP release from A549 cells involves synergistic autocrine stimulation by coreleased uridine nucleotidesThe Journal of Physiology, 2007
- Coordinated release of nucleotides and mucin from human airway epithelial Calu‐3 cellsThe Journal of Physiology, 2007
- GPR40 Is Necessary but Not Sufficient for Fatty Acid Stimulation of Insulin Secretion In VivoDiabetes, 2007
- Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre RecombinasePublished by Elsevier BV ,1999