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

dc.contributor.authorSegura Covarrubias, Ma. Guadalupe
dc.contributor.authorAréchiga Figueroa, Iván Arael
dc.contributor.authorDe Jesús Pérez, José Juan
dc.contributor.authorSánchez Solano, Alfredo
dc.contributor.authorPérez Cornejo, Gloria Patricia
dc.contributor.authorArreola, Jorge
dc.date.accessioned2021-04-26T19:14:20Z
dc.date.available2021-04-26T19:14:20Z
dc.date.issued2020
dc.identifier.citationSegura-Covarrubias, G., Aréchiga-Figueroa, I.A., De Jesús-Pérez, J.J. et al. Voltage-Dependent Protonation of the Calcium Pocket Enable Activation of the Calcium-Activated Chloride Channel Anoctamin-1 (TMEM16A). Sci Rep 10, 6644 (2020). https://doi.org/10.1038/s41598-020-62860-9
dc.identifier.urihttp://hdl.handle.net/11627/5608
dc.description.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 intracellular acidification enabled activation of TMEM16A by voltage-dependent protonation, which enhanced the open probability of the channel. Mutating Glu/Asp residues in the Ca2+-binding pocket to glutamine (to resemble a permanent protonated Glu) yielded channels that were easier to activate at physiological pH. Notably, the response of these mutants to intracellular acidification was diminished and became voltage-independent. Thus, voltage-dependent protonation of glutamate/aspartate residues (Glu/Asp) located in the Ca2+-binding pocket underlines TMEM16A activation in the absence of intracellular Ca2+."
dc.publisherNature Publishing Group
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCa2+-activated Cl- channel
dc.subjectInhibition
dc.subjectCurrents
dc.subjectContributes
dc.subjectExpression
dc.subjectMechanism
dc.subjectCells
dc.subject.classificationCIENCIAS TECNOLÓGICAS
dc.titleVoltage-Dependent Protonation of the Calcium Pocket Enable Activation of the Calcium-Activated Chloride Channel Anoctamin-1 (TMEM16A)
dc.typearticle
dc.identifier.doihttps://doi.org/10.1038/s41598-020-62860-9
dc.rights.accessAcceso Abierto


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 Internacional