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(Circulation. 2000;102:921.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome

H. Abriel, MD, PhD; X. H. T. Wehrens, MSc; J. Benhorin, MD; B. Kerem, PhD; R. S. Kass, PhD

From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY (H.A., X.H.T.W., R.S.K.), and the Heiden Department of Cardiology, Bikur Cholim Hospital (J.B.), and Department of Genetics, Hebrew University (B.K.), Jerusalem, Israel. The first 2 authors contributed equally to this work.

Correspondence to R.S. Kass, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, New York, NY 10032. E-mail rsk20{at}columbia.edu

Background—Multiple mutations of SCN5A, the gene that encodes the human Na⁺ channel -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 -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 (EC₅₀, WT=894 and DG=205 µmol/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 (EC₅₀, WT=11.0 and DG=1.7 µmol/L), but not lidocaine (EC₅₀, WT=318.0 and DG=176 µmol/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 -subunit C-terminus in the flecainide/channel interaction.

Key Words: sodium • ion channels • antiarrhythmia agents • pharmacology • electrophysiology • genes

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