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Mutations in Cardiac Sodium Channels

Clinical Implications

  • Practical Pharmacogenomics
  • Published:
American Journal of Pharmacogenomics

Abstract

Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins responsible for the rapid action potential upstroke in most excitable cells. Recently discovered mutations in VGSCs, which underlie idiopathic clinical disease, have emphasized the importance of these channels in tissues such as skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding the cardiac sodium channel isoform (SCN5A) have been linked to at least three abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada’s syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations in SCN5A manifest as one or more of these clinical phenotypes — the precise distinction between these diseases is increasingly subtle.

Clinical management of LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show more sensitivity to flecainide than wild-type (WT) channels, while lidocaine sensitivity is unchanged. One plausible explanation for differential drug sensitivity is that mutant channels may allow more access to a receptor site compared with WT through altered protein allosteric changes during an action potential. The high affinity binding site for local anesthetic block has been identified in the pore region of the channel. This region is not water accessible during the closed state, thus requiring channel opening for charged drug (flecainide and mexiletine) access and block. Channel mutations which disrupt inactivation biophysics lead to increased drug binding by altering the time the binding site is accessible during an action potential.

Neutral drugs (lidocaine) which are not dependent on channel opening for binding site access will not be sensitive to mutations that alter channel inactivation properties. Interestingly another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, suggesting that although drug effects of SCN5A mutations cross disease boundaries, clinical management with flecainide will be beneficial to patients in a mutation-specific manner.

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Acknowledgements

The authors have no conflicts of interest directly relevant to the content of this review. This manuscript was in part supported by grants (1R01-HL 56810-5 and 1P01-HL 67849-02) from the National Institutes of Health and National Heart, Lung, and Blood Institute.

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  1. Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, New York, 10032, USA

    Huajun Liu, Colleen E. Clancy, Joseph W. Cormier &  Robert S. Kass

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  1. Huajun Liu
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  2. Colleen E. Clancy
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Correspondence to Robert S. Kass.

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Liu, H., Clancy, C.E., Cormier, J.W. et al. Mutations in Cardiac Sodium Channels. Am J Pharmacogenomics 3, 173–179 (2003). https://doi.org/10.2165/00129785-200303030-00003

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