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

ABSTRACT: Glucose homeostasis depends critically on insulin that is secreted by pancreatic ?-cells. Serum glucose, which is directly sensed by ?-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 ?-cell swelling elicits canonical LRRC8A-dependent VRAC currents that depolarize ?-cells to an extent that causes electrical excitation. Glucose-induced excitation and Ca2+ responses are delayed in onset, but not abolished, in ?-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 ?-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 ?-cells synergistically with KATP closure. Neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signaling within islets.

SUBMITTER: Stuhlmann T 

PROVIDER: S-EPMC5958052 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature