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.


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.
Abriel
H
H
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Wehrens
X H
XH
Benhorin
J
J
Kerem
B
B
Kass
R S
RS
D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology; D008040:Genetic Linkage; D006801:Humans; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017354:Point Mutation; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics*; D013379:Substrate Specificity
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine; D005424:Flecainide