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- Title
A calcium sensor in the sodium channel modulates cardiac excitability.
- Authors
Tan, Hanno L; Kupershmidt, Sabina; Zhang, Rong; Stepanovic, Svetlana; Roden, Dan M; Wilde, Arthur A M; Anderson, Mark E; Balser, Jeffrey R
- 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' domain 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. 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, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.
- Publication
Nature, 2002, Vol 415, Issue 6870, p442
- ISSN
0028-0836
- Publication type
Journal Article
- DOI
10.1038/415442a