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.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY-NC-SA 4.0
ID Serval
serval:BIB_8BFC1005353C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
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.
Périodique
Journal of General Physiology
Auteur(s)
Liu H., Tateyama M., Clancy C.E., Abriel H., Kass R.S.
ISSN
0022-1295
Statut éditorial
Publié
Date de publication
2002
Peer-reviewed
Oui
Volume
120
Numéro
1
Pages
39-51
Langue
anglais
Notes
Journal Article Research Support, U.S. Gov't, P.H.S. --- Old month value: Jul
Résumé
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.
Mots-clé
Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cell Line, Flecainide, Humans, Long QT Syndrome, Mutation, Myocardium, Sodium Channel Blockers, Sodium Channels
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 11:56
Dernière modification de la notice
20/08/2019 15:50
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