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

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Serval ID
serval:BIB_13D1C39CC70C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.
Journal
Circulation
Author(s)
Wehrens X.H., Abriel H., Cabo C., Benhorin J., Kass R.S.
ISSN
1524-4539[electronic]
Publication state
Published
Issued date
2000
Volume
102
Number
5
Pages
584-590
Language
english
Abstract
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.
Keywords
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
Create date
24/01/2008 10:56
Last modification date
20/08/2019 12:42
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