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A calcium sensor in the sodium channel modulates cardiac excitability

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.

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Figure 1: Inactivation gating of hH1 is sensitive to Ca2+ and CaM.
Figure 2: Conditional changes in slow inactivation in wild-type and mutant hH1 channels.
Figure 3: A mutation in the IQ domain alters Ca2+/CaM sensitivity.
Figure 4: Inactivation gating properties of the A1924T mutation in the IQ domain.

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Acknowledgements

We acknowledge C. R. Bezzina for genetic analysis of A1924T, C. A. Conrath for subcloning A1924T, and A. George for critique. H.L.T. was supported by a fellowship from the Royal Netherlands Academy of Arts and Sciences. Additional financial support was provided by the Interuniversity Cardiology Institute Netherlands project 27 (H.L.T. and A.A.M.W.), the Dutch Heart Foundation NHS (A.A.M.W.), and National Institutes of Health grants (M.E.A. and J.R.B.).

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Correspondence to Jeffrey R. Balser.

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Tan, H., Kupershmidt, S., Zhang, R. et al. A calcium sensor in the sodium channel modulates cardiac excitability. Nature 415, 442–447 (2002). https://doi.org/10.1038/415442a

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