Modulation of HERG channel inactivation by external cations

We investigated the effect of external cations on the permeability characteristics and gating kinetics of the human ether- à- go- go-related gene (HERG) current using the whole-cell patch-clamp technique. Inward HERG currents were recorded on hyperpolarization in 140 mM external Cs(+) and Rb(+), as well as K(+). The permeability ratios of Rb(+) and Cs(+) relative to K(+) were 1.25 and 0.56, respectively. Biphasic outward currents were recorded on depolarization in 140 mM Cs(+) and in Rb(+ )with much smaller amplitude. The voltage dependence of inactivation was affected by external cations, such that the half-inactivation voltage shifted from -69.4+/-3.7 mV in K(+) to -30.7+/-1.6 mV in Cs(+) and to -35.8+/-1.9 mV in Rb(+) ( n=5). The time constants of inactivation were also changed significantly by external cations; tau of inactivation at +40 mV was 16.4+/-2.2 ms in 140 mM K(+), 181+/-20.3 ms in Cs(+), and 94.1+/-7.6 ms in Rb(+) ( n=5). Voltage dependence of activation was not altered significantly. The inhibition of the rapid inactivation mechanism by large cations may suggest that the "foot-in-the-door" model of gating is involved in HERG channel inactivation.