@article {Kang155093, author = {Chen Kang and Susheel K. Gunasekar and Anil Mishra and Litao Xie and Yanhui Zhang and Saachi Pai and Yiwen Gao and Andrew W. Norris and Samuel B. Stephens and Rajan Sah}, title = {SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion}, elocation-id = {155093}, year = {2017}, doi = {10.1101/155093}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 {\textquotedblleft}swell-secretion{\textquotedblright} coupling as required for glucose-stimulated insulin secretion.}, URL = {https://www.biorxiv.org/content/early/2017/06/24/155093}, eprint = {https://www.biorxiv.org/content/early/2017/06/24/155093.full.pdf}, journal = {bioRxiv} }