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| Item Type: | Article |
|---|---|
| Title: | LRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion |
| Creators Name: | Stuhlmann, T., Planells-Cases, R. and Jentsch, T.J. |
| 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 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 β-cell swelling elicits canonical LRRC8A-dependent VRAC currents that depolarize β-cells to an extent that causes electrical excitation. Glucose-induced excitation and Ca(2+) 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 K(ATP) closure. Neurotransmitter-permeable LRRC8D-containing VRACs might have additional roles in autocrine/paracrine signaling within islets. |
| Keywords: | Animal Models, Blood Glucose, Glucose, Hypoglycemic Agents, Inbred C57BL Mice, Insulin, Insulin-Secreting Cells, Inwardly Rectifying Potassium Channels, Ion Channels, Membrane Proteins, Primary Cell Culture, Protein Multimerization, Tolbutamide, Transgenic Mice, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 9 |
| Number: | 1 |
| Page Range: | 1974 |
| Date: | 17 May 2018 |
| Official Publication: | https://doi.org/10.1038/s41467-018-04353-y |
| PubMed: | View item in PubMed |
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