Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.

Détails

ID Serval
serval:BIB_13D1C39CC70C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.
Périodique
Circulation
Auteur(s)
Wehrens X.H., Abriel H., Cabo C., Benhorin J., Kass R.S.
ISSN
1524-4539[electronic]
Statut éditorial
Publié
Date de publication
2000
Volume
102
Numéro
5
Pages
584-590
Langue
anglais
Résumé
BACKGROUND: D1790G, a mutation of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na(+) channel activity but instead alters the kinetics and voltage-dependence of the inactivated state. METHODS AND RESULTS: We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na(+) channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na(+) channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na(+) entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents. CONCLUSIONS: We conclude that the D1790G mutation of the Na(+) channel alpha-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na(+) channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.
Mots-clé
Action Potentials, Calcium, Cell Line, Cell Membrane, Heart Rate, Humans, Kinetics, Long QT Syndrome, Patch-Clamp Techniques, Point Mutation, Recombinant Proteins, Sodium Channels, Transfection, Ventricular Function
Pubmed
Web of science
Création de la notice
24/01/2008 10:56
Dernière modification de la notice
20/08/2019 12:42
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