Voltage-Dependent Protonation of the Calcium Pocket Enable Activation of the Calcium-Activated Chloride Channel Anoctamin-1 (TMEM16A).

ABSTRACT: Anoctamin-1 (ANO1 or TMEM16A) is a homo-dimeric Ca²⁺-activated Cl^- channel responsible for essential physiological processes. Each monomer harbours a pore and a Ca²⁺-binding pocket; the voltage-dependent binding of two intracellular Ca²⁺ ions to the pocket gates the pore. However, in the absence of intracellular Ca²⁺ voltage activates TMEM16A by an unknown mechanism. Here we show voltage-activated anion currents that are outwardly rectifying, time-independent with fast or absent tail currents that are inhibited by tannic and anthracene-9-carboxylic acids. Since intracellular protons compete with Ca²⁺ for binding sites in the pocket, we hypothesized that voltage-dependent titration of these sites would induce gating. Indeed i

SUBMITTER: Segura-Covarrubias G 

PROVIDER: S-EPMC7170896 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature