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Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers

Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers...

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Detalles Bibliográficos
Autores principales: Pedersen, Thomas Holm, de Paoli, Frank Vincenzo, Flatman, John A., Nielsen, Ole Bækgaard
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757767/
https://www.ncbi.nlm.nih.gov/pubmed/19786584
http://dx.doi.org/10.1085/jgp.200910290
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author Pedersen, Thomas Holm
de Paoli, Frank Vincenzo
Flatman, John A.
Nielsen, Ole Bækgaard
author_facet Pedersen, Thomas Holm
de Paoli, Frank Vincenzo
Flatman, John A.
Nielsen, Ole Bækgaard
author_sort Pedersen, Thomas Holm
collection PubMed
description Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(−) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of ∼70% caused G(m) to decline by ∼55% in a manner that is well described by a single exponential function characterized by a time constant of ∼200 APs (phase 1). When stimulation was continued beyond ∼1,800 APs, synchronized elevations in G(K) (∼14-fold) and G(Cl) (∼3-fold) caused G(m) to rise sigmoidally to ∼400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in ∼1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(−) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP-firing fast-twitch muscle fibers. Such regulation may contribute to the physiological control of excitability in active muscle.
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spelling pubmed-27577672010-04-01 Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers Pedersen, Thomas Holm de Paoli, Frank Vincenzo Flatman, John A. Nielsen, Ole Bækgaard J Gen Physiol Article Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(−) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of ∼70% caused G(m) to decline by ∼55% in a manner that is well described by a single exponential function characterized by a time constant of ∼200 APs (phase 1). When stimulation was continued beyond ∼1,800 APs, synchronized elevations in G(K) (∼14-fold) and G(Cl) (∼3-fold) caused G(m) to rise sigmoidally to ∼400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in ∼1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(−) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP-firing fast-twitch muscle fibers. Such regulation may contribute to the physiological control of excitability in active muscle. The Rockefeller University Press 2009-10 /pmc/articles/PMC2757767/ /pubmed/19786584 http://dx.doi.org/10.1085/jgp.200910290 Text en © 2009 Pedersen et al. 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
Pedersen, Thomas Holm
de Paoli, Frank Vincenzo
Flatman, John A.
Nielsen, Ole Bækgaard
Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title_full Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title_fullStr Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title_full_unstemmed Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title_short Regulation of ClC-1 and K(ATP) channels in action potential–firing fast-twitch muscle fibers
title_sort regulation of clc-1 and k(atp) channels in action potential–firing fast-twitch muscle fibers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757767/
https://www.ncbi.nlm.nih.gov/pubmed/19786584
http://dx.doi.org/10.1085/jgp.200910290
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