Cytoplasmic ATP-sensing Domains Regulate Gating of Skeletal Muscle ClC-1 Chloride Channels

• Published in: The Journal of biological chemistry 2005-09, Vol.280 (37), p.32452-32458
• Main Authors: Bennetts, Brett, Rychkov, Grigori Y., Ng, Hooi-Ling, Morton, Craig J., Stapleton, David, Parker, Michael W., Cromer, Brett A.
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - chemistry; Adenosine Monophosphate - chemistry; Adenosine Triphosphate - chemistry; Amino Acid Sequence; Animals; Chloride Channels - chemistry; Chloride Channels - metabolism; Cystathionine beta-Synthase - chemistry; Cytoplasm - metabolism; Dose-Response Relationship, Drug; Humans; Immunoprecipitation; Ion Channel Gating; Ligands; Models, Molecular; Molecular Sequence Data; Muscle, Skeletal - metabolism; Mutagenesis, Site-Directed; Mutation; Protein Binding; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Software
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M502890200

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 β-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.