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

Nature Communications
Till StuhlmannThomas J Jentsch

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.

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Citations

Jun 9, 2018·The Journal of Biological Chemistry·Jennifer C LückThomas J Jentsch
Jun 22, 2018·The Journal of Biological Chemistry·Pingzheng ZhouThomas J Jentsch
May 22, 2019·Adipocyte·Susheel K GunasekarRajan Sah
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Aug 27, 2021·Frontiers in Cardiovascular Medicine·Daniel TurnerRajan Sah

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