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

Abstract

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 (EC 50 , 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 (EC 50 , WT=11.0 and DG=1.7 μmol/L), but not lidocaine (EC 50 , 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 α-subunit C-terminus in the flecainide/channel interaction.