A calcium sensor in the sodium channel modulates cardiac excitability

Hanno L. Tan, Sabina Kupershmidt, Rong Zhang, Svetlana Stepanovic, Dan M. Roden, Arthur A. M. Wilde, Mark E. Anderson and Jeffrey R. Balser ()
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Hanno L. Tan: The Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam
Sabina Kupershmidt: Vanderbilt University School of Medicine
Rong Zhang: Vanderbilt University School of Medicine
Svetlana Stepanovic: Vanderbilt University School of Medicine
Dan M. Roden: Vanderbilt University School of Medicine
Arthur A. M. Wilde: The Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam
Mark E. Anderson: Vanderbilt University School of Medicine
Jeffrey R. Balser: Vanderbilt University School of Medicine

Nature, 2002, vol. 415, issue 6870, 442-447

Abstract: Abstract Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal ‘IQ’ domain1 of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation—a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias2,3. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome4,5, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.

Date: 2002
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DOI: 10.1038/415442a

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