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• W2682061666 abstract "Abstract Insulin secretion from the pancreatic β-cell initiated by activation of voltage-gated Ca 2+ channels (VGCC) to trigger Ca 2+ -mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC depends on the β-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents 1-3 . While much attention has focused on inhibitory potassium currents 4-10 there is little knowledge about the excitatory currents required to depolarize the β-cell, including the molecular identity of these excitatory currents 3 . Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (I Cl,SWELL) in β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated I Cl,SWELL and this is required for both glucose-stimulated and hypotonic swell-mediated activation of VGCC-dependent intracellular calcium signaling in β-cells. SWELL1 KO MIN6 cells and β-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin content in vitro . Tamoxifen-inducible β-cell targeted SWELL1 KO mice have normal fasting insulin levels but display markedly impaired glucose-stimulated insulin secretion. Our results reveal a physiological role for SWELL1 as a glucose sensor - linking glucose-mediated β-cell swelling to SWELL1-dependent activation of VGCC-triggered calcium signaling, and highlights SWELL1-mediated “swell-secretion” coupling as required for glucose-stimulated insulin secretion." @default.
• W2682061666 created "2017-06-30" @default.
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• W2682061666 date "2017-06-24" @default.
• W2682061666 modified "2023-09-23" @default.
• W2682061666 title "SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion" @default.
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• W2682061666 doi "https://doi.org/10.1101/155093" @default.
• W2682061666 hasPublicationYear "2017" @default.
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