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Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate

The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of c...

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Autores principales: Zangerl-Plessl, Eva-Maria, Wu, Wei, Sanguinetti, Michael C., Stary-Weinzinger, Anna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996038/
https://www.ncbi.nlm.nih.gov/pubmed/36911523
http://dx.doi.org/10.3389/fmolb.2023.1137368
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author Zangerl-Plessl, Eva-Maria
Wu, Wei
Sanguinetti, Michael C.
Stary-Weinzinger, Anna
author_facet Zangerl-Plessl, Eva-Maria
Wu, Wei
Sanguinetti, Michael C.
Stary-Weinzinger, Anna
author_sort Zangerl-Plessl, Eva-Maria
collection PubMed
description The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of channel closure (deactivation) of hERG1 channels. Compounds that increase hERG1 channel currents represent a novel approach for prevention of arrhythmia associated with prolonged ventricular repolarization. RPR260243 (RPR), a quinoline oxo-propyl piperidine derivative, inhibits inactivation and dramatically slows the rate of hERG1 channel deactivation. Here we report that similar to its effect on wild-type channels, RPR greatly slows the deactivation rate of hERG1 channels missing their amino-termini, or of split channels lacking a covalent link between the voltage sensor domain and the pore domain. By contrast, RPR did not slow deactivation of C-terminal truncated hERG1 channels or D540K hERG1 mutant channels activated by hyperpolarization. Together, these findings indicate that ability of RPR to slow deactivation requires an intact C-terminus, does not slow deactivation by stabilizing an interaction involving the amino-terminus or require a covalent link between the voltage sensor and pore domains. All-atom molecular dynamics simulations using the cryo-EM structure of the hERG1 channel revealed that RPR binds to a pocket located at the intracellular ends of helices S5 and S6 of a single subunit. The slowing of channel deactivation by RPR may be mediated by disruption of normal S5-S6 interactions.
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spelling pubmed-99960382023-03-10 Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate Zangerl-Plessl, Eva-Maria Wu, Wei Sanguinetti, Michael C. Stary-Weinzinger, Anna Front Mol Biosci Molecular Biosciences The opening and closing of voltage-dependent potassium channels is dependent on a tight coupling between movement of the voltage sensing S4 segments and the activation gate. A specific interaction between intracellular amino- and carboxyl-termini is required for the characteristically slow rate of channel closure (deactivation) of hERG1 channels. Compounds that increase hERG1 channel currents represent a novel approach for prevention of arrhythmia associated with prolonged ventricular repolarization. RPR260243 (RPR), a quinoline oxo-propyl piperidine derivative, inhibits inactivation and dramatically slows the rate of hERG1 channel deactivation. Here we report that similar to its effect on wild-type channels, RPR greatly slows the deactivation rate of hERG1 channels missing their amino-termini, or of split channels lacking a covalent link between the voltage sensor domain and the pore domain. By contrast, RPR did not slow deactivation of C-terminal truncated hERG1 channels or D540K hERG1 mutant channels activated by hyperpolarization. Together, these findings indicate that ability of RPR to slow deactivation requires an intact C-terminus, does not slow deactivation by stabilizing an interaction involving the amino-terminus or require a covalent link between the voltage sensor and pore domains. All-atom molecular dynamics simulations using the cryo-EM structure of the hERG1 channel revealed that RPR binds to a pocket located at the intracellular ends of helices S5 and S6 of a single subunit. The slowing of channel deactivation by RPR may be mediated by disruption of normal S5-S6 interactions. Frontiers Media S.A. 2023-02-23 /pmc/articles/PMC9996038/ /pubmed/36911523 http://dx.doi.org/10.3389/fmolb.2023.1137368 Text en Copyright © 2023 Zangerl-Plessl, Wu, Sanguinetti and Stary-Weinzinger. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Zangerl-Plessl, Eva-Maria
Wu, Wei
Sanguinetti, Michael C.
Stary-Weinzinger, Anna
Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title_full Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title_fullStr Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title_full_unstemmed Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title_short Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate
title_sort binding of rpr260243 at the intracellular side of the herg1 channel pore domain slows closure of the helix bundle crossing gate
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996038/
https://www.ncbi.nlm.nih.gov/pubmed/36911523
http://dx.doi.org/10.3389/fmolb.2023.1137368
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