The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice

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 Gα q and Gα 11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Gα q /Gα 11 -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 Gα q /Gα 11 , and closure of K ATP 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 G q /G 11 -coupled P2Y6 receptor and extracellular calcium acting through the calciumsensing receptor. Thus, the G q /G 11 -mediated signaling pathway potentiates insulin secretion in response to glucose by integrating systemic as well as autocrine/paracrine mediators. IntroductionThe adequate secretion of insulin from pancreatic β cells is essential for the maintenance of normoglycemia; impaired insulin secretion results in diabetes mellitus with hyperglycemia, dyslipidemia, and consequent long-term tissue damage (1). The on-demand release of insulin from β cells is mainly regulated by blood glucose levels: high concentrations of glucose result in enhanced intracellular glucose metabolism with accumulation of ATP and consecutive closure of ATP-sensitive K + channels, leading to the opening of voltage-operated Ca 2+ channels and Ca 2+ -mediated exocytosis of insulin-containing vesicles (2, 3).While the ATP-dependent mechanism is clearly the master regulator of insulin release, various mediators potentiate insulin release in response to glucose. For example, gastrointestinal hormones such as glucose-dependent insulinotropic polypeptide (GIP) or glucagon-like peptide-1 (GLP-1) potentiate insulin secretion by activation of GPCRs, which signal through the G s family of heterotrimeric G proteins (4-6). The potentiating effect of G s on glucose-induced insulin release depends on activation of adenylyl cyclase and consecutive phosphorylation of voltage-operated Ca 2+ channels (7, 8) or opening of nonselective cation channels (9).Another important group of modulators are neurotransmitters and neuropeptides (10, 11), most prominent among them being the neurotransmitter acetylcholine, which is released from vagal nerve terminals and potentiates insulin secretion through the muscarinic receptor subtype M 3 (12)(13)(14)(15). In contrast to the receptors for GIP and GLP-1, the M 3 receptor does not elicit G smediated adenylyl cyclase activation, but was shown to signal through the G q /G 11 family of heterotrimeric G proteins. Th...

Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

“…Glucose-stimulated insulin secretion was lower in islets from G␣ q /G␣ 11 knockout mice than those from WT mice even at physiological pH (22), supporting the involvement of G q/11 protein activation through unidentified GPCR in glucose-stimulated insulin secretion under the condition. The present study suggests that one of the unidentified GPCR may be OGR1.…”

ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

“…It is possible that isolated alpha cells, as a consequence of the deprivation of factors released from beta cells (including insulin), have an increased K ATP channel activity. Indeed, nucleotides and Ca 2+ co-released with insulin potentiate insulin secretion in an autocrine fashion mediated by G q /G 11 -coupled receptors [82]. When this signalling was prevented by genetic ablation of G q /G 11 , beta cell excitability was reduced via increased K ATP channel activity.…”

The G Protein-coupled Receptor P2Y14 Influences Insulin Release and Smooth Muscle Function in Mice

“…After a 30-min equilibration period in KRB solution containing 2.8 mM glucose, pancreatic islets were stimulated with KRB solution containing either 2.8 or 16.7 mM glucose or 100 M UDP-glucose in the presence of 16.7 mM glucose for 30 min. The supernatants were then collected for measurement of secreted insulin, and islets were lysed in acid-ethanol to extract the residual islet insulin (19,20). Insulin concentrations were determined with an insulin AlphaLISA kit (PerkinElmer Life Sciences).…”