Basic arrhythmogenic mechanisms in both inherited and acquired long QT syndrome

The heterologous expression system will provide clues for understanding the basic mechanism of arrhythmogenicity in both inherited and acquired long QT syndrome, which are reviewed here, with emphasis on the K⁺ channels. Endothelin is implicated in the morphological and electrical remodeling of cardiac muscles in heart failure. The effects of endothelin on the transient outward K⁺ currents (I_to) were compared between Kv1.4 (rich in endocardial muscle) and Kv4.3 (rich in epicardial muscle) channels in the Xenopus oocytes expression system. Both I_tos were decreased by stimulation of endothelin receptor ET_A coexpressed with the K ⁺ channels. I_to of Kv1.4 was decreased by about 85% after 10^-8 M ET-1, whereas that of Kv4.3 was decreased by about 60%. By mutagenesis experiments, we identified two phosphorylation sites of PKC and CaMKII in Kv1.4 responsible for the decrease in Ito by ET-1. In Kv4.3 we identified a PKC phosphorylation site that is partly responsible for the decrease. Differences in the suppression of I_to could be due to the differences in intracellular signaling including the number of phosphorylation sites. These findings show some of the molecular mechanisms of ventricular arrhythmias in heart failure, resulting in dispersion and prolongation of action potential which elicit reentry and afterdepolarization.