Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome.

Détails

ID Serval
serval:BIB_EF43C3EA058B
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome.
Périodique
Circulation
Auteur(s)
Abriel H., Wehrens X.H., Benhorin J., Kerem B., Kass R.S.
ISSN
1524-4539[electronic]
Statut éditorial
Publié
Date de publication
2000
Volume
102
Numéro
8
Pages
921-925
Langue
anglais
Résumé
BACKGROUND: Multiple mutations of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, are linked to 1 form of the congenital long-QT syndrome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal region of the Na(+) channel alpha-subunit, alters steady-state inactivation of expressed channels but does not promote sustained Na(+) channel activity. Recently, flecainide, but not lidocaine, has been found to correct the disease phenotype, delayed ventricular repolarization, in DG carriers. METHODS AND RESULTS: To understand the molecular basis of this difference, we studied both drugs using wild-type (WT) and mutant Na(+) channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidocaine (EC(50), WT=894 and DG=205 micromol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a concentration range that is therapeutically relevant, DG channels are blocked selectively by flecainide (EC(50), WT=11.0 and DG=1.7 micromol/L), but not lidocaine (EC(50), WT=318.0 and DG=176 micromol/L) during repetitive stimulation. CONCLUSIONS: These results (1) demonstrate that the DG mutation confers a unique pharmacological response on expressed channels; (2) suggest that flecainide use-dependent block of DG channels underlies its therapeutic effects in carriers of this gene mutation; and (3) suggest a role of the Na(+) channel alpha-subunit C-terminus in the flecainide/channel interaction.
Mots-clé
Anti-Arrhythmia Agents, Cell Line, Dose-Response Relationship, Drug, Flecainide, Humans, Kinetics, Lidocaine, Linkage (Genetics), Long QT Syndrome, Membrane Potentials, Point Mutation, Sodium Channel Blockers, Sodium Channels, Substrate Specificity
Pubmed
Web of science
Création de la notice
24/01/2008 10:56
Dernière modification de la notice
20/08/2019 16:17
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