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J. Biol. Chem., Vol. 280, Issue 37, 32452-32458, September 16, 2005

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

Brett Bennetts, Grigori Y. Rychkov1, Hooi-Ling Ng, Craig J. Morton, David Stapleton¶, Michael W. Parker23, and Brett A. Cromer34

From the St. Vincent's Institute, 9 Princes St. Fitzroy, Victoria, 3065, Australia, The University of Adelaide, Adelaide, South Australia, 5005, Australia, and ^¶Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.

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 -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.

Received for publication, March 16, 2005 , and in revised form, June 8, 2005.

^* This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) (to M. W. P. and B. A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ An Australian Research Council Research Fellow.

² An NHMRC Senior Principal Research Fellow.

³ Joint senior authors.

⁴ To whom correspondence should be addressed. Tel.: 61-3-9288-2480; Fax: 61-3-9416-2676; E-mail; bcromer{at}svi.edu.au.

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