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https://hdl.handle.net/2440/27552
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Type: | Journal article |
Title: | Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels |
Author: | Bennetts, B. Rychkov, G. Ng, H. Morton, C. Stapleton, D. Parker, M. Cromer, B. |
Citation: | Journal of Biological Chemistry, 2005; 280(37):32452-32458 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2005 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Brett Bennetts, Grigori Y. Rychkov, Hooi-Ling Ng, Craig J. Morton, David Stapleton, Michael W. Parker, and Brett A. Cromer |
Abstract: | ClC proteins are a family of chloride channels and transporters that are found in a wide variety of prokaryotic and eukaryotic cell types. The mammalian voltage-gated chloride channel ClC-1 is important for controlling the electrical excitability of skeletal muscle. Reduced excitability of muscle cells during metabolic stress can protect cells from metabolic exhaustion and is thought to be a major factor in fatigue. Here we identify a novel mechanism linking excitability to metabolic state by showing that ClC-1 channels are modulated by ATP. The high concentration of ATP in resting muscle effectively inhibits ClC-1 activity by shifting the voltage gating to more positive potentials. ADP and AMP had similar effects to ATP, but IMP had no effect, indicating that the inhibition of ClC-1 would only be relieved under anaerobic conditions such as intense muscle activity or ischemia, when depleted ATP accumulates as IMP. The resulting increase in ClC-1 activity under these conditions would reduce muscle excitability, thus contributing to fatigue. We show further that the modulation by ATP is mediated by cystathionine ß-synthase-related domains in the cytoplasmic C terminus of ClC-1. This defines a function for these domains as gating-modulatory domains sensitive to intracellular ligands, such as nucleotides, a function that is likely to be conserved in other ClC proteins. |
Keywords: | Muscle, Skeletal Cytoplasm Animals Humans Cystathionine beta-Synthase Chloride Channels Adenosine Diphosphate Adenosine Monophosphate Adenosine Triphosphate Ligands Mutagenesis, Site-Directed Immunoprecipitation Ion Channel Gating Amino Acid Sequence Protein Structure, Tertiary Protein Binding Sequence Homology, Amino Acid Dose-Response Relationship, Drug Mutation Models, Molecular Software Molecular Sequence Data |
Rights: | © 2005 by The American Society for Biochemistry and Molecular Biology, Inc. |
DOI: | 10.1074/jbc.M502890200 |
Published version: | http://www.jbc.org/cgi/content/abstract/280/37/32452 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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