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Liu H, Tateyama M, Clancy CE, et al. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations. J Gen Physiol. 2002;120(1):39-51doi: 10.1085/jgp.20028558.
Liu, H., Tateyama, M., Clancy, C. E., Abriel, H., & Kass, R. S. (2002). Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations. The Journal of general physiology, 120(1), 39-51. https://doi.org/10.1085/jgp.20028558
Liu, Huajun, et al. "Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations." The Journal of general physiology vol. 120,1 (2002): 39-51. doi: https://doi.org/10.1085/jgp.20028558
Liu H, Tateyama M, Clancy CE, Abriel H, Kass RS. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations. J Gen Physiol. 2002 Jul;120(1):39-51. doi: 10.1085/jgp.20028558. PMID: 12084774; PMCID: PMC2311398.
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J Gen Physiol. 2002 Jul;120(1):39-51. doi: 10.1085/jgp.20028558.

Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations.

The Journal of general physiology

Huajun Liu, Michihiro Tateyama, Colleen E Clancy, Hugues Abriel, Robert S Kass

Affiliations

  1. Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

PMID: 12084774 PMCID: PMC2311398 DOI: 10.1085/jgp.20028558

Abstract

Na(+) channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the alpha subunit of the cardiac voltage-gated Na(+) channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na(+) channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.

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