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