Abstract
Background Nifekalant is a blocker of cardiac Ikr channels encoded by a HERG gene and is reported to be clinically effective for lethal ventricular tachyarrhythmias. However, nifekalant-binding sites in a HERG channel have not been identified. Thus, we attempted to identify these sites and compare them with those for MK-499, a methanesulfonanilide anti-arrhythmic drug.
Methods and Results We individually substituted 24 residues in the pore helix and S6 domain of HERG to alanine. The currents through the mutant HERG channels expressed in Xenopus oocytes were measured with the standard two-microelectrode voltage clamp technique. The effect of ~85% inhibitory concentration (11 μM) of nifekalant was assessed with each mutant. Three mutations located in the pore helix (T623A, S624A, and V625A) and 3 mutations in the S6 domain (G648A, Y652A, and F656A) decreased the channel's sensitivity to nifekalant.
Conclusions The six identified residues likely form nifekalant-binding sites in a HERG channel as is the case for MK-499. [Jpn J Physiol 54 Suppl:S126 (2004)]
