Electrophysiologic characterization of a novel hERG channel activator

Abstract

Activators of the human ether-a-go-go-related gene (hERG) K + channel have been reported recently to enhance hERG current amplitude (five synthetic small molecules and one naturally occurring substance). Here, we characterize the effects of a novel compound A-935142 ({4-[4-(5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-cyclohexyl}-acetic acid) on guinea-pig atrial and canine ventricular action potentials (microelectrode techniques) and hERG channels expressed in HEK-293 cells (whole-cell patch clamp techniques). A-935142 shortened cardiac action potentials and enhanced the amplitude of the hERG current in a concentration- and voltage-dependent manner. The fully activated current–voltage relationship revealed that this compound (60 μM) increased both outward and inward K + current as well as the slope conductance of the linear portion of the fully activated I– V relation. A-935142 significantly reduced the time constants ( τ) of hERG channel activation at two example voltages (−10 mV: τ = 100 ± 17 ms vs. 164 ± 24 ms, n = 6, P < 0.01; +30 mV: τ = 16.7 ± 1.8 ms vs. 18.9 ± 1.8 ms, n = 5, P < 0.05) and shifted the voltage-dependence for hERG activation in the hyperpolarizing direction by 9 mV. The time course of hERG channel deactivation was slowed at multiple potentials (−120 to −70 mV). A-935142 also reduced the rate of inactivation and shifted the voltage-dependence of inactivation in the depolarizing direction by 15 mV. Recovery of hERG channel from inactivation was not affected by A-935142. In conclusion, A-935142 enhances hERG current in a complex manner by facilitation of activation, reduction of inactivation, and slowing of deactivation, and abbreviates atrial and ventricular repolarization.