| First Author | Stuhlmann T | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1974 |
| PubMed ID | 29773801 | Mgi Jnum | J:263622 |
| Mgi Id | MGI:6160993 | Doi | 10.1038/s41467-018-04353-y |
| Citation | Stuhlmann T, et al. (2018) LRRC8/VRAC anion channels enhance beta-cell glucose sensing and insulin secretion. Nat Commun 9(1):1974 |
| abstractText | Glucose homeostasis depends critically on insulin that is secreted by pancreatic beta-cells. Serum glucose, which is directly sensed by beta-cells, stimulates depolarization- and Ca(2+)-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 beta-cell swelling elicits canonical LRRC8A-dependent VRAC currents that depolarize beta-cells to an extent that causes electrical excitation. Glucose-induced excitation and Ca(2+) responses are delayed in onset, but not abolished, in beta-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 beta-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 beta-cells synergistically with KATP closure. Neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signaling within islets. |
