1. Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, USA
2. Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, USA
3. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, USA
4. The Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, the Netherlands

Correspondence to: Jeffrey R. Balser^1,3 Correspondence and requests for materials should be addressed to J.R.B. (e-mail: Email: jeff.balser@mcmail.vanderbilt.edu).

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 arrhythmias^{2, 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 syndrome^{4, 5}, but at the same time inhibited slow inactivation induced by Ca²⁺/CaM, yielding a clinically benign (arrhythmia free) phenotype.