PT - JOURNAL ARTICLE AU - Chen Kang AU - Susheel K. Gunasekar AU - Anil Mishra AU - Litao Xie AU - Yanhui Zhang AU - Saachi Pai AU - Yiwen Gao AU - Andrew W. Norris AU - Samuel B. Stephens AU - Rajan Sah TI - <em>SWELL1</em> is a glucose sensor required for β-cell excitability and insulin secretion AID - 10.1101/155093 DP - 2017 Jan 01 TA - bioRxiv PG - 155093 4099 - http://biorxiv.org/content/early/2017/06/24/155093.short 4100 - http://biorxiv.org/content/early/2017/06/24/155093.full AB - Insulin secretion from the pancreatic β-cell 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 depends on the β-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents1-3. While much attention has focused on inhibitory potassium currents4-10 there is little knowledge about the excitatory currents required to depolarize the β-cell, including the molecular identity of these excitatory currents3. Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,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.