Ultra-rapid delayed rectifier channels: molecular basis and therapeutic implications.

The ultrarapid delayed rectifier channels have attracted considerable interest as targets for 'atrial-selective' antiarrhythmic drugs because they contribute to atrial but not to ventricular repolarization. Thus, I(Kur) channel blockers are expected to prolong selectively the atrial effective refractory period without inducing proarrhythmic effects due to excessive ventricular action potential prolongation. Here we provide an overview of the properties of I(Kur) channels in expression systems and native cardiomyocytes. The ion conducting pore of the channel is formed by four Kv1.5 α-subunits, whereas the ancillary β-subunits Kvβ1.2, Kvβ1.3, and Kvβ2.1 control channel trafficking and plasma membrane integration as well as activation and inactivation kinetics. Investigation of I(Kur) channel blockers in cardiomyocytes is complicated (i) by substantial overlap of I(Kur) with other currents, notably the transient outward current I(to), (ii) by lack of drug selectivity, and (iii) by disease-induced regulation of I(Kur). Some new compounds developed as I(Kur) blockers are described and their efficacy in treatment of atrial fibrillation (AF) is discussed. Current evidence suggests that pure I(Kur) channel block may not be sufficient to suppress AF.