Referenced in: none

Automatically associated channels: ClC1 , ClC4

Title: Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels.

Authors: Brett Bennetts, Grigori Y Rychkov, Hooi-Ling Ng, Craig J Morton, David Stapleton, Michael W Parker, Brett A Cromer

Journal, date & volume: J. Biol. Chem., 2005 Sep 16 , 280, 32452-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16027167

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 beta-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.