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 IKur channels in expression systems and native cardiomyocytes. The ion conducting pore of the channel is formed by four Kv1.5 alpha-subunits, whereas the ancillary beta-subunits Kv beta 1.2, Kv beta 1.3, and Kv beta 2.1 control channel trafficking and plasma membrane integration as well as activation and inactivation kinetics. Investigation of IKur channel blockers in cardiomyocytes is complicated (i) by substantial overlap of IKur with other currents, notably the transient outward current I(to), (ii) by lack of drug selectivity, and (iii) by disease-induced regulation of IKur. Some new compounds developed as IKur blockers are described and their efficacy in treatment of atrial fibrillation (AF) is discussed. Current evidence suggests that pure IKur channel block may not be sufficient to suppress AF.