SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia

Abstract

Insulin secretion is initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC requires β-cell membrane depolarization, which is regulated by a balance of depolarizing and hyperpolarizing ionic currents. Here, we show that SWELL1 mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in both murine and human β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELL and this contributes to membrane depolarization and activation of VGCC-dependent intracellular calcium signaling. SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. Tamoxifen-inducible β-cell-targeted Swell1 KO mice have normal fasting serum glucose and insulin levels but impaired glucose-stimulated insulin secretion and glucose tolerance; and this is further exacerbated in mild obesity. Our results reveal that β-cell SWELL1 modulates insulin secretion and systemic glycaemia by linking glucose-mediated β-cell swelling to membrane depolarization and activation of VGCC-triggered calcium signaling.

Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells

“…Our efforts to delete CDK1 were frustrated by the embryonic lethality of mice lacking ␤-cell CDK1 (CDK1-floxed mice (36); Ins1-Cre mice (37)) and by the inefficacy of Ins1-CreER mice (Jax 026802) (37) to catalyze loxP excision. Inconsistent outcomes with Ins1-CreER mice are becoming widely known, 6 although there are published successes (38). Even so, direct complex I inhibition with rotenone mimicked the effect of CDK1 inhibition on islet respiration, NADH utilization, ATP/ADP, and calcium influx.…”

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

“…Therefore, subsequent studies employed conditional, region-and cell type-specific Lrrc8a gene deletion. This approach revealed tissue-specific contributions of VRAC to reproductive function (spermatogenesis), regulation of adipocyte size, insulin signaling, glucose homeostasis, and innate immunity (Luck et al 2018;Bao et al 2018;Zhang et al 2017;Kang et al 2018;Zhou et al 2020). Although the central nervous system (CNS) has long been considered to be the tissue with the highest sensitivity to cell volume alterations and VRAC activity (Kimelberg and Mongin 1998;Kimelberg 2005;Mongin 2007;Mongin 2016;Wilson and Mongin 2018), few studies have analyzed the functional significance of LRRC8 proteins in the brain.…”

Flow fluorometry quantification of anion channel VRAC subunit LRRC8A at the membrane of living U937 cells

“…Since the molecular structure of VRAC was identified, a series of antibodies against different regions of the basic subunits of the family LRRC8 have been developed and effectively used [4,5,9,14,17,18,[23][24][25][26]. Before now, VRAC subunit proteins were detected mostly by immunoblotting of the solubilized whole cells [27][28][29][30][31][32], less often of cell membranes lysates [14,33,34] or by imaging cells that have been permeabilized for staining [35,36]. Furthermore, these data were mostly obtained from cells specifically rich in VRAC such as epithelial cells, astrocytes, vascular smooth muscle cells and transfected cells.…”