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A calcium sensor in the sodium channel modulates cardiac excitability

Author

Listed:
  • 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
    Vanderbilt University School of Medicine)

  • Svetlana Stepanovic

    (Vanderbilt University School of Medicine)

  • Dan M. Roden

    (Vanderbilt University School of Medicine
    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
    Vanderbilt University School of Medicine)

  • Jeffrey R. Balser

    (Vanderbilt University School of Medicine)

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.

Suggested Citation

  • Hanno L. Tan & Sabina Kupershmidt & Rong Zhang & Svetlana Stepanovic & Dan M. Roden & Arthur A. M. Wilde & Mark E. Anderson & Jeffrey R. Balser, 2002. "A calcium sensor in the sodium channel modulates cardiac excitability," Nature, Nature, vol. 415(6870), pages 442-447, January.
    • Handle: RePEc:nat:nature:v:415:y:2002:i:6870:d:10.1038_415442a
    DOI: 10.1038/415442a
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