Anoctamin 1 (Ano1) is required for glucose-induced membrane potential oscillations and insulin secretion by murine β-cells

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Abstract

Anions such as Cl − and HCO 3 − are well known to play an important role in glucose-stimulated insulin secretion (GSIS). In this study, we demonstrate that glucose-induced Cl − efflux from β-cells is mediated by the Ca 2+ -activated Cl − channel anoctamin 1 (Ano1). Ano1 expression in rat β-cells is demon-strated by reverse transcriptase–polymerase chain reaction, west-ern blotting, and immunohistochemistry. Typical Ano1 currents are observed in whole-cell and inside-out patches in the presence of intracellular Ca ++ : at 1 μM, the Cl − current is outwardly rec-tifying, and at 2 μM, it becomes almost linear. The relative per-meabilities of monovalent anions are NO 3 − (1.83±0.10) > Br − (1.42±0.07) > Cl − (1.0). A linear single-channel current–voltage relationship shows a conductance of 8.37 pS. These currents are nearly abolished by blocking Ano1 antibodies or by the inhibi-tors 2-(5-ethyl-4-hydroxy-6-methylpyrimidin-2-ylthio)-N-(4-(4-methoxyphenyl)thiazol-2-yl)acetamide (T-AO1) and tannic acid (TA). These inhibitors induce a strong decrease of 16.7-mM glucose-stimulated action potential rate (at least 87 % on dis-persed cells) and a partial membrane repolarization with T-AO1. They abolish or strongly inhibit the GSIS increment at 8.3 mM and at 16.7 mM glucose. Blocking Ano1 antibodies also abolish the 16.7-mM GSIS increment. Combined treatment with bumetanide and acetazolamide in low Cl − and HCO 3 − media provokes a 65 % reduction in action potential (AP) amplitude and a 15-mV AP peak repolarization. Although the mechanism triggering Ano1 opening remains to be established, the present data demonstrate that Ano1 is required to sustain glucose-stimulated membrane potential oscillations and insulin secretion.

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Crutzen, R., Virreira, M., Markadieu, N., Shlyonsky, V., Sener, A., Malaisse, W. J., … Golstein, P. E. (2016). Anoctamin 1 (Ano1) is required for glucose-induced membrane potential oscillations and insulin secretion by murine β-cells. Pflugers Archiv European Journal of Physiology, 468(4), 573–591. https://doi.org/10.1007/s00424-015-1758-5

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