title: 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 beta cell-specific inactivation of the genes encoding the G protein alpha-subunits Galphaq and Galpha11 resulted in impaired glucose tolerance and insulin secretion in mice. Interestingly, the defects observed in Galphaq/Galpha11-deficient beta 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 beta cells was impaired in the absence of Galphaq/Galpha11, and closure of KATP channels was inhibited. We provide evidence that this reduced excitability was due to a loss of beta 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.
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Sassmann
authors.forename: Belinda
authors.initials: B
authors.lastname: Gier
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Gisela
authors.initials: G
authors.lastname: Drews
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose; D006728:Hormones; D007328:Insulin / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D006728:Hormones; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D044169:Receptors, Calcium-Sensing; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose; D002118:Calcium