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

• Published in: Circulation (New York, N.Y.) Vol. 102; no. 8; pp. 921 - 925
• Main Authors: ABRIEL, H, WEHRENS, X. H. T, BENHORIN, J, KEREM, B, KASS, R. S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 22.08.2000; American Heart Association, Inc
• Subjects: Anti-Arrhythmia Agents - pharmacology; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cell Line; Dose-Response Relationship, Drug; Flecainide - pharmacology; Genetic Linkage; Heart; Humans; Kinetics; Lidocaine - pharmacology; Long QT Syndrome - drug therapy; Long QT Syndrome - genetics; Medical sciences; Membrane Potentials - drug effects; Membrane Potentials - physiology; NAV1.5 Voltage-Gated Sodium Channel; Point Mutation; Sodium Channel Blockers; Sodium Channels - genetics; Substrate Specificity; Human; Arrhythmia; Prolonged QT interval; Electrophysiology; Cardiovascular disease; Ionic channel; Pharmacology; Antiarrhythmic agent; Conduction disorder; Gene; Heart block; Heart disease; Sodium ion; Mutation; Flecainide
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.102.8.921

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. 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. 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.