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 α-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 α-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 carders of this gene mutation; and (3) suggest a role of the Na⁺ channel α-subunit C-terminus in the flecainide/channel interaction.