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J. Biol. Chem., Vol. 281, Issue 33, 24015-24023, August 18, 2006
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From the Department of Pharmacology, Columbia University, New York, New York 10032
Perturbation of sodium channel inactivation, a finely tuned process that critically regulates the flow of sodium ions into excitable cells, is a common functional consequence of inherited mutations associated with epilepsy, skeletal muscle disease, autism, and cardiac arrhythmias. Understanding the structural basis of inactivation is key to understanding these disorders. Here we identify a novel role for a structural motif in the COOH terminus of the heart NaV1.5 sodium channel in determining channel inactivation. Structural modeling predicts an interhelical hydrophobic interface between paired EF hands in the proximal region of the NaV1.5 COOH terminus. The predicted interface is conserved among almost all EF hand-containing proteins and is the locus of a number of disease-associated mutations. Using the structural model as a guide, we provide biochemical and biophysical evidence that the structural integrity of this interface is necessary for proper Na+ channel inactivation gating. We thus demonstrate a novel role of the sodium channel COOH terminus structure in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it.
Received for publication, June 7, 2006
* This work was supported by United States Public Health Service NHLBI, National Institutes of Health, Grant R01-056810-07. 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.
1 Present address: St. Vincent's Medical Center, 2800 Main St., Bridgeport, CT 06606-4201.
2 Present address: National Institute for Physiological Sciences, Department of Molecular Physiology, Division of Biophysics and Neurobiology, 38 Nishigonaka Myodajii, Ozazaki, 444-8585 Japan.
3 To whom correspondence should be addressed: Dept. of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032. Tel.: 212-305-7444; Fax: 212-342-2703; E-mail: rsk20{at}columbia.edu.
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