A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes

1 The human ether à‐go‐go‐related gene ( HERG ) encodes a K + o channel that is believed to be the basis of the delayed rectified current, I Kr , in cardiac muscle. We studied HERG expressed in Xenopus oocytes using a two‐electrode and cut‐open oocyte clamp technique with [K + ] o of 2 and 98 m m . 2 The time course of activation of the channel was measured using an envelope of tails protocol and demonstrated that activation of the heterologously expressed HERG current ( I HERG ) was sigmoidal in onset. At least three closed states were required to reproduce the sigmoid time course. 3 The voltage dependence of the activation process and its saturation at positive voltages suggested the existence of at least one relatively voltage‐insensitive step. A three closed state activation model with a single voltage‐insensitive intermediate closed state was able to reproduce the time and voltage dependence of activation, deactivation and steady‐state activation. Activation was insensitive to changes in [K + ] o . 4 Both inactivation and recovery time constants increased with a change of [K + ] o from 2 to 98 m m . Steady‐state inactivation shifted by ∼30 mV in the depolarized direction with a change from 2 to 98 m m K* o5 Simulations showed that modulation of inactivation is a minimal component of the increase of this current by [K + ] o , and that a large increase in total conductance must also occur.