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Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener

KCNQ2-5 (Kv7.2–Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels...

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Detalles Bibliográficos
Autores principales: Wang, Alice W., Yau, Michael C., Wang, Caroline K., Sharmin, Nazlee, Yang, Runying Y., Pless, Stephan A., Kurata, Harley T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168237/
https://www.ncbi.nlm.nih.gov/pubmed/30166313
http://dx.doi.org/10.1085/jgp.201812014
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author Wang, Alice W.
Yau, Michael C.
Wang, Caroline K.
Sharmin, Nazlee
Yang, Runying Y.
Pless, Stephan A.
Kurata, Harley T.
author_facet Wang, Alice W.
Yau, Michael C.
Wang, Caroline K.
Sharmin, Nazlee
Yang, Runying Y.
Pless, Stephan A.
Kurata, Harley T.
author_sort Wang, Alice W.
collection PubMed
description KCNQ2-5 (Kv7.2–Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels but absent in the retigabine-insensitive KCNQ1 subtype. Recent work has demonstrated that certain KCNQ openers are insensitive to mutations of this conserved Trp, and that their effects are instead abolished or attenuated by mutations in the voltage-sensing domain (VSD). In this study, we investigate the stoichiometry of a VSD-targeted KCNQ2 channel activator, ICA-069673, by forming concatenated channel constructs with varying numbers of drug-insensitive subunits. In homomeric WT KCNQ2 channels, ICA-069673 strongly stabilizes an activated channel conformation, which is reflected in the pronounced deceleration of deactivation and leftward shift of the conductance–voltage relationship. A full complement of four drug-sensitive subunits is required for maximal sensitivity to ICA-069673—even a single drug-insensitive subunit leads to significantly weakened effects. In a companion article (see Yau et al. in this issue), we demonstrate very different stoichiometry for the action of retigabine on KCNQ3, for which a single retigabine-sensitive subunit enables near-maximal effect. Together, these studies highlight fundamental differences in the site and mechanism of activation between retigabine and voltage sensor–targeted KCNQ openers.
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spelling pubmed-61682372019-04-01 Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener Wang, Alice W. Yau, Michael C. Wang, Caroline K. Sharmin, Nazlee Yang, Runying Y. Pless, Stephan A. Kurata, Harley T. J Gen Physiol Research Articles KCNQ2-5 (Kv7.2–Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels but absent in the retigabine-insensitive KCNQ1 subtype. Recent work has demonstrated that certain KCNQ openers are insensitive to mutations of this conserved Trp, and that their effects are instead abolished or attenuated by mutations in the voltage-sensing domain (VSD). In this study, we investigate the stoichiometry of a VSD-targeted KCNQ2 channel activator, ICA-069673, by forming concatenated channel constructs with varying numbers of drug-insensitive subunits. In homomeric WT KCNQ2 channels, ICA-069673 strongly stabilizes an activated channel conformation, which is reflected in the pronounced deceleration of deactivation and leftward shift of the conductance–voltage relationship. A full complement of four drug-sensitive subunits is required for maximal sensitivity to ICA-069673—even a single drug-insensitive subunit leads to significantly weakened effects. In a companion article (see Yau et al. in this issue), we demonstrate very different stoichiometry for the action of retigabine on KCNQ3, for which a single retigabine-sensitive subunit enables near-maximal effect. Together, these studies highlight fundamental differences in the site and mechanism of activation between retigabine and voltage sensor–targeted KCNQ openers. Rockefeller University Press 2018-10-01 /pmc/articles/PMC6168237/ /pubmed/30166313 http://dx.doi.org/10.1085/jgp.201812014 Text en © 2018 Wang et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Wang, Alice W.
Yau, Michael C.
Wang, Caroline K.
Sharmin, Nazlee
Yang, Runying Y.
Pless, Stephan A.
Kurata, Harley T.
Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title_full Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title_fullStr Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title_full_unstemmed Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title_short Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
title_sort four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted kcnq opener
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168237/
https://www.ncbi.nlm.nih.gov/pubmed/30166313
http://dx.doi.org/10.1085/jgp.201812014
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