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An outer-pore gate modulates the pharmacology of the TMEM16A channel
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Dinsdale, Ria L., Pipatpolkai, Tanadet, Agostinelli, Emilio, Russell, Angela J., Stansfeld, Phillip J. and Tammaro, Paolo (2021) An outer-pore gate modulates the pharmacology of the TMEM16A channel. Proceedings of the National Academy of Sciences of the United States of America, 118 (34). e2023572118. doi:10.1073/pnas.2023572118 ISSN 0027-8424.
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Official URL: http://dx.doi.org/10.1073/pnas.2023572118
Abstract
TMEM16A Ca2+-activated chloride channels are involved in multiple cellular functions and are proposed targets for diseases such as hypertension, stroke, and cystic fibrosis. This therapeutic endeavor, however, suffers from paucity of selective and potent modulators. Here, exploiting a synthetic small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we shed light on sites of the channel amenable for pharmacological intervention. Mutant channels with the intracellular gate constitutively open were generated. These channels were entirely insensitive to extracellular A9C when intracellular Ca2+ was omitted. However, when physiological Ca2+ levels were reestablished, the mutants regained sensitivity to A9C. Thus, intracellular Ca2+ is mandatory for the channel response to an extracellular modulator. The underlying mechanism is a conformational change in the outer pore that enables A9C to enter the pore to reach its binding site. The explanation of this structural rearrangement highlights a critical site for pharmacological intervention and reveals an aspect of Ca2+ gating in the TMEM16A channel.
Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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Subjects: | Q Science > QP Physiology | |||||||||||||||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Chemistry > Computational and Theoretical Chemistry Centre |
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Library of Congress Subject Headings (LCSH): | Cellular signal transduction , Molecular dynamics , Membrane proteins -- Physiological transport, Ion channels, Membranes (Biology), Chloride channels | |||||||||||||||||||||||||||||||||
Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | |||||||||||||||||||||||||||||||||
Publisher: | National Academy of Sciences | |||||||||||||||||||||||||||||||||
ISSN: | 0027-8424 | |||||||||||||||||||||||||||||||||
Official Date: | 24 August 2021 | |||||||||||||||||||||||||||||||||
Dates: |
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Volume: | 118 | |||||||||||||||||||||||||||||||||
Number: | 34 | |||||||||||||||||||||||||||||||||
Article Number: | e2023572118 | |||||||||||||||||||||||||||||||||
DOI: | 10.1073/pnas.2023572118 | |||||||||||||||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||||||||||||||
Date of first compliant deposit: | 16 September 2021 | |||||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 24 February 2022 | |||||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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