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

Chen Kang, Litao Xie, Susheel K. Gunasekar, Anil Mishra, Yanhui Zhang, Saachi Pai, Yiwen Gao, Ashutosh Kumar, Andrew W. Norris, Samuel B. Stephens and Rajan Sah ()
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Chen Kang: University of Iowa, Carver College of Medicine
Litao Xie: University of Iowa, Carver College of Medicine
Susheel K. Gunasekar: University of Iowa, Carver College of Medicine
Anil Mishra: University of Iowa, Carver College of Medicine
Yanhui Zhang: University of Iowa, Carver College of Medicine
Saachi Pai: University of Iowa, Carver College of Medicine
Yiwen Gao: University of Iowa, Carver College of Medicine
Ashutosh Kumar: University of Iowa, Carver College of Medicine
Andrew W. Norris: University of Iowa, Carver College of Medicine
Samuel B. Stephens: University of Iowa, Carver College of Medicine
Rajan Sah: University of Iowa, Carver College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02664-0

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