Molecular pharmacology of the sodium channel mutation D1790G linked to thelong-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 synd rome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal region of th e Na+ channel alpha-subunit. alters steady-state inactivation of expressed channels but does not promote sustained Na+ channel activity. Recently, fle cainide, but not lidocaine, has been found to correct the disease phenotype , delayed ventricular repolarization, in DC carriers. Methods and Results-To understand the molecular basis of this difference, w e studied both drugs using wild-type (WT) and mutant Na+ channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidoca ine (EC50, WT=894 and DG=205 mu mol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a conc entration range that is therapeutically relevant, DG channels are blocked s electively by flecainide (EC50 WT=11.0 and DG=1.7 mu mol/L), but not lidoca ine (EC50, WT=318.0 and DG=176 mu mol/L) during repetitive stimulation. Conclusions-These results (1) demonstrate that the DG mutation confers a un ique pharmacological response on expressed channels; (2) suggest that fleca inide use-dependent block of DG channels underlies its therapeutic effects in carriers of this gene mutation; and (3) suggest a role of the Na+ channe l alpha-subunit C-terminus in the flecainide/channel interaction.