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bioRxiv · 10.1101/155093

SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion

Kang, C.·Gunasekar, S. K.·Mishra, A.·Xie, L.·Zhang, Y.·Pai, S.·Gao, Y.·Norris, A. W.·Stephens, S. B.·Sah, R.
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Abstract

Insulin secretion from the pancreatic {beta}-cell initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the {beta}-cell plasma membrane. The firing of VGCC depends on the {beta}-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 {beta}-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 {beta}-cells. Hypotonic and glucose-stimulated {beta}-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 {beta}-cells. SWELL1 KO MIN6 cells and {beta}-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin content in vitro. Tamoxifen-inducible {beta}-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 {beta}-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.

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Kang, C., Gunasekar, S. K., Mishra, A., Xie, L., Zhang, Y., Pai, S., Gao, Y., Norris, A. W., Stephens, S. B., Sah, R.. 2017-06-24. SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion. https://doi.org/10.1101/155093

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