Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1)
type: Document
related by: authorship_69435
has publication venue: Journal of General Physiology
type: Continuant
crisid: 10060
artnum: e202113027
volume: 154
abstract: Numerous essential physiological processes depend on the TMEM16A-mediated Ca2 -activated chloride fluxes. Extensive structure–function studies have helped to elucidate the Ca2 gating mechanism of TMEM16A, revealing a Ca2 -sensing element close to the anion pore that alters conduction. However, substrate selection and the substrate–gating relationship in TMEM16A remain less explored. Here, we study the gating–permeant anion relationship on mouse TMEM16A expressed in HEK 293 cells using electrophysiological recordings coupled with site-directed mutagenesis. We show that the apparent Ca2 sensitivity of TMEM16A increased with highly permeant anions and SCN− mole fractions, likely by stabilizing bound Ca2 . Conversely, mutations at crucial gating elements, including the Ca2 -binding site 1, the transmembrane helix 6 (TM6), and the hydrophobic gate, impaired the anion permeability and selectivity of TMEM16A. Finally, we found that, unlike anion-selective wild-type channels, the voltage dependence of unselective TMEM16A mutant channels was less sensitive to SCN−. Therefore, our work identifies structural determinants of selectivity at the Ca2 site, TM6, and hydrophobic gate and reveals a reciprocal regulation of gating and selectivity. We suggest that this regulation is essential to set ionic selectivity and the Ca2 and voltage sensitivities in TMEM16A. © 2022De Jesús-Pérez et al.
abstract: Numerous essential physiological processes depend on the TMEM16A-mediated Ca2%2b-activated chloride fluxes. Extensive structure–function studies have helped to elucidate the Ca2%2b gating mechanism of TMEM16A, revealing a Ca2%2b-sensing element close to the anion pore that alters conduction. However, substrate selection and the substrate–gating relationship in TMEM16A remain less explored. Here, we study the gating–permeant anion relationship on mouse TMEM16A expressed in HEK 293 cells using electrophysiological recordings coupled with site-directed mutagenesis. We show that the apparent Ca2%2b sensitivity of TMEM16A increased with highly permeant anions and SCN− mole fractions, likely by stabilizing bound Ca2%2b. Conversely, mutations at crucial gating elements, including the Ca2%2b-binding site 1, the transmembrane helix 6 (TM6), and the hydrophobic gate, impaired the anion permeability and selectivity of TMEM16A. Finally, we found that, unlike anion-selective wild-type channels, the voltage dependence of unselective TMEM16A mutant channels was less sensitive to SCN−. Therefore, our work identifies structural determinants of selectivity at the Ca2%2b site, TM6, and hydrophobic gate and reveals a reciprocal regulation of gating and selectivity. We suggest that this regulation is essential to set ionic selectivity and the Ca2%2b and voltage sensitivities in TMEM16A. © 2022De Jesús-Pérez et al.
related by: authorship_69437
type: Thing
doi: 10.1085/jgp.202113027
origen: scopus
most specific type: Document
type: Article
freetext keyword: anion; ANO1 protein, human; ANO1 protein, mouse; anoctamin 1; calcium; chloride channel; tumor protein; animal; chemistry; genetics; HEK293 cell line; human; metabolism; mouse; Animals; Anions; Anoctamin-1; Calcium; Chloride Channels; HEK293 Cells; Humans; Mice; Neoplasm Proteins
related by: authorship_69438
estado: published
most specific type: Article
type: Entity
pmid: 35687042
related by: authorship_69434
e iscopus: 2-s2.0-85131902341
type: Generically Dependent Continuant
issue: 8
related by: authorship_69436
type: Information Content Entity
has funding vehicle: Consejo Nacional de Ciencia y Tecnología, CONACYT: 234820, 297721, 711128, 933084
accesstype: All Open Access, Bronze
date time value: article date 10060
chemicalscas: calcium, 7440-70-2, 14092-94-5; Anions; ANO1 protein, human; ANO1 protein, mouse; Anoctamin-1; Calcium; Chloride Channels; Neoplasm Proteins
related by: authorship_69439

Document
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Journal of General Physiology
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type: Generically Dependent Continuant
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type: Journal
publication venue for: Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1)
type: Thing
type: Document
type: Continuant
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Continuant
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Generically Dependent Continuant
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RDF description of Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1) - http://orbis.uaslp.mx/vivo/individual/scopus10059
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date: 2026-08-24T21:50:57
publisher: vivo
type: Document

Article
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Consejo Nacional de Ciencia y Tecnología, CONACYT: 234820, 297721, 711128, 933084
type: Relationship
type: BFO_0000020
type: Entity
type: Thing
type: Grant
type: Continuant
funding vehicle for: Gating and anion selectivity are reciprocally regulated in TMEM16A (ANO1)

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