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Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore

Many physiological and synthetic agents act by occluding the ion conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies with membrane voltage. Two models have been proposed to explain this voltage sensitivity. One model assumes tha...

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Autores principales: Martínez-François, Juan Ramón, Lu, Zhe
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812505/
https://www.ncbi.nlm.nih.gov/pubmed/20100894
http://dx.doi.org/10.1085/jgp.200910324
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author Martínez-François, Juan Ramón
Lu, Zhe
author_facet Martínez-François, Juan Ramón
Lu, Zhe
author_sort Martínez-François, Juan Ramón
collection PubMed
description Many physiological and synthetic agents act by occluding the ion conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies with membrane voltage. Two models have been proposed to explain this voltage sensitivity. One model assumes that the charged blocker itself directly senses the transmembrane electric field, i.e., that blocker binding is intrinsically voltage dependent. In the alternative model, the blocker does not directly interact with the electric field; instead, blocker binding acquires voltage dependence solely through the concurrent movement of permeant ions across the field. This latter model may better explain voltage dependence of channel block by large organic compounds that are too bulky to fit into the narrow (usually ion-selective) part of the pore where the electric field is steep. To date, no systematic investigation has been performed to distinguish between these voltage-dependent mechanisms of channel block. The most fundamental characteristic of the extrinsic mechanism, i.e., that block can be rendered voltage independent, remains to be established and formally analyzed for the case of organic blockers. Here, we observe that the voltage dependence of block of a cyclic nucleotide–gated channel by a series of intracellular quaternary ammonium blockers, which are too bulky to traverse the narrow ion selectivity filter, gradually vanishes with extreme depolarization, a predicted feature of the extrinsic voltage dependence model. In contrast, the voltage dependence of block by an amine blocker, which has a smaller “diameter” and can therefore penetrate into the selectivity filter, follows a Boltzmann function, a predicted feature of the intrinsic voltage dependence model. Additionally, a blocker generates (at least) two blocked states, which, if related serially, may preclude meaningful application of a commonly used approach for investigating channel gating, namely, inferring the properties of the activation gate from the kinetics of channel block.
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spelling pubmed-28125052010-08-01 Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore Martínez-François, Juan Ramón Lu, Zhe J Gen Physiol Article Many physiological and synthetic agents act by occluding the ion conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies with membrane voltage. Two models have been proposed to explain this voltage sensitivity. One model assumes that the charged blocker itself directly senses the transmembrane electric field, i.e., that blocker binding is intrinsically voltage dependent. In the alternative model, the blocker does not directly interact with the electric field; instead, blocker binding acquires voltage dependence solely through the concurrent movement of permeant ions across the field. This latter model may better explain voltage dependence of channel block by large organic compounds that are too bulky to fit into the narrow (usually ion-selective) part of the pore where the electric field is steep. To date, no systematic investigation has been performed to distinguish between these voltage-dependent mechanisms of channel block. The most fundamental characteristic of the extrinsic mechanism, i.e., that block can be rendered voltage independent, remains to be established and formally analyzed for the case of organic blockers. Here, we observe that the voltage dependence of block of a cyclic nucleotide–gated channel by a series of intracellular quaternary ammonium blockers, which are too bulky to traverse the narrow ion selectivity filter, gradually vanishes with extreme depolarization, a predicted feature of the extrinsic voltage dependence model. In contrast, the voltage dependence of block by an amine blocker, which has a smaller “diameter” and can therefore penetrate into the selectivity filter, follows a Boltzmann function, a predicted feature of the intrinsic voltage dependence model. Additionally, a blocker generates (at least) two blocked states, which, if related serially, may preclude meaningful application of a commonly used approach for investigating channel gating, namely, inferring the properties of the activation gate from the kinetics of channel block. The Rockefeller University Press 2010-02 /pmc/articles/PMC2812505/ /pubmed/20100894 http://dx.doi.org/10.1085/jgp.200910324 Text en © 2010 Martínez-François and Lu 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.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Martínez-François, Juan Ramón
Lu, Zhe
Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title_full Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title_fullStr Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title_full_unstemmed Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title_short Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
title_sort intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812505/
https://www.ncbi.nlm.nih.gov/pubmed/20100894
http://dx.doi.org/10.1085/jgp.200910324
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