HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 33, 24015-24023, August 18, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/33/24015    most recent M605473200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Glaaser, I. W. Articles by Kass, R. S. Search for Related Content PubMed PubMed Citation Articles by Glaaser, I. W. Articles by Kass, R. S. Social Bookmarking                      What's this?

A Carboxyl-terminal Hydrophobic Interface Is Critical to Sodium Channel Function

Relevance to Inherited Disorders^*

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 Na_V1.5 sodium channel in determining channel inactivation. Structural modeling predicts an interhelical hydrophobic interface between paired EF hands in the proximal region of the Na_V1.5 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Chagot, F. Potet, J. R. Balser, and W. J. Chazin Solution NMR Structure of the C-terminal EF-hand Domain of Human Cardiac Sodium Channel NaV1.5 J. Biol. Chem., March 6, 2009; 284(10): 6436 - 6445. [Abstract] [Full Text] [PDF]

				V. Z. Miloushev, J. A. Levine, M. A. Arbing, J. F. Hunt, G. S. Pitt, and A. G. Palmer III Solution Structure of the NaV1.2 C-terminal EF-hand Domain J. Biol. Chem., March 6, 2009; 284(10): 6446 - 6454. [Abstract] [Full Text] [PDF]

				A. Lee and A. L. Goldin Role of the amino and carboxy termini in isoform-specific sodium channel variation J. Physiol., August 15, 2008; 586(16): 3917 - 3926. [Abstract] [Full Text] [PDF]

				B.-H. Tan, P. Iturralde-Torres, A. Medeiros-Domingo, S. Nava, D. J. Tester, C. R. Valdivia, T. Tusie-Luna, M. J. Ackerman, and J. C. Makielski A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia Cardiovasc Res, December 1, 2007; 76(3): 409 - 417. [Abstract] [Full Text] [PDF]

				R. Rusconi, P. Scalmani, R. R. Cassulini, G. Giunti, A. Gambardella, S. Franceschetti, G. Annesi, E. Wanke, and M. Mantegazza Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+ Channel Mutant J. Neurosci., October 10, 2007; 27(41): 11037 - 11046. [Abstract] [Full Text] [PDF]

				K. M. Kahlig, S. N. Misra, and A. L. George Jr Impaired Inactivation Gate Stabilization Predicts Increased Persistent Current for an Epilepsy-Associated SCN1A Mutation J. Neurosci., October 25, 2006; 26(43): 10958 - 10966. [Abstract] [Full Text] [PDF]