PHARMACOLOGICAL TARGETING OF LONG QT MUTANT SODIUM-CHANNELS

The congenital long QT syndrome (LOTS) is an inherited disorder charac terized by a delay in cardiac cellular repolarization leading to cardi ac arrhythmias and sudden death often in young people. One form of the disease (LQT3) involves mutations in the voltage-gated cardiac sodium channel. The potential for targeted suppression of the LQT defect was explored by heterologous expression of mutant channels in cultured hu man cells. Kinetic and steady state analysis revealed an enhanced appa rent affinity for the predominantly charged, primary amine compound, m exiletine. The affinity of the mutant channels in the inactivated stat e was similar to the wild type (WT) channels (IC50 similar to 15-20 mu M), but the late-opening channels were inhibited at significantly low er concentrations (IC50 = 2-3 mu M) causing a preferential suppression of the late openings. The targeting of the defective behavior of the mutant channels has important implications for therapeutic interventio n in this disease. The results provide insights for the selective supp ression of the mutant phenotype by very low concentrations of drug and indicate that mexiletine equally suppresses the defect in all three k nown LQT3 mutants.