A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents

Nifekalant and azimilide, Class III antiarrhythmic agents, block the human ether-à-go-go-related gene K+ (hERG) channel. However, when a depolarizing membrane potential is applied, they also increase the current at low potentials by shifting its activation curve towards hyperpolarizing voltages. This phenomenon is called ‘facilitation’. In this study, we tried to address the mechanism underlying the facilitation by analyzing the effects of various compounds on hERG expressed in Xenopus oocytes. Like nifekalant, amiodarone, quinidine and carvedilol, but not by dofetilide, caused the current facilitation of hERG, suggesting that the facilitation is a common effect to a subset of hERG blockers. As the concentration of each compound was increased, the total hERG current was suppressed progressively, while the current at low potentials was augmented. Activation curves of the remaining hERG current in the facilitation condition could be described as the sum of two Boltzmann functions reflecting two populations of hERG currents having different activation curves. The voltage shift in the activation curve from control was constant for each compound even at different concentrations; −31 mV in amiodarone, −27 mV in nifekalant, −17 mV in quinidine and −12 mV in carvedilol. Therefore, the facilitation is based on the appearance of hERG whose voltage-dependence for the activation is shifted towards hyperpolarizing voltages.

► We examined the mechanism of the compound-induced facilitation of the hERG current. ► Amiodarone, nifekalant, carvedilol and quinidine facilitate hERG currents. ► Facilitation is a negative shift of the voltage-dependent activation curve. ► Depolarization promotes the formation of a drug-channel interaction for facilitation.