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Nat Commun. 2018 May 17;9(1):1974. doi: 10.1038/s41467-018-04353-y.

LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion.

Author information

1
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
2
Graduate Program of the Faculty for Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
3
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany. jentsch@fmp-berlin.de.
4
Neurocure Cluster of Excellence, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany. jentsch@fmp-berlin.de.

Abstract

Glucose homeostasis depends critically on insulin that is secreted by pancreatic β-cells. Serum glucose, which is directly sensed by β-cells, stimulates depolarization- and Ca2+-dependent exocytosis of insulin granules. Here we show that pancreatic islets prominently express LRRC8A and LRRC8D, subunits of volume-regulated VRAC anion channels. Hypotonicity- or glucose-induced β-cell swelling elicits canonical LRRC8A-dependent VRAC currents that depolarize β-cells to an extent that causes electrical excitation. Glucose-induced excitation and Ca2+ responses are delayed in onset, but not abolished, in β-cells lacking the essential VRAC subunit LRRC8A. Whereas Lrrc8a disruption does not affect tolbutamide- or high-K+-induced insulin secretion from pancreatic islets, it reduces first-phase glucose-induced insulin secretion. Mice lacking VRAC in β-cells have normal resting serum glucose levels but impaired glucose tolerance. We propose that opening of LRRC8/VRAC channels increases glucose sensitivity and insulin secretion of β-cells synergistically with KATP closure. Neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signaling within islets.

PMID:
29773801
PMCID:
PMC5958052
DOI:
10.1038/s41467-018-04353-y
[Indexed for MEDLINE]
Free PMC Article

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