The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice.
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.
Sassmann
Antonia
A
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Gier
Belinda
B
Gröne
Hermann-Josef
HJ
Drews
Gisela
G
Offermanns
Stefan
S
Wettschureck
Nina
N
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*
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