Modulation of HERG channel inactivation by external cations

Abstract

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; τ 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.

Appendix

Appendix 1: model formulations for HERG channel

I _HERG=G _HERG mh(V−E _K)

G _HERG=0.032

E _K=0 ([K⁺]_i=140 mM, [K⁺]_o=140 mM)

α_m=0.00425 exp{(V−23.3)/11.9}

β_m=0.00002 exp{(V+23.6)/(−15.4)}

α_h=0.087 exp{(V−23.6)/(−100)}

β_h=0.033 exp{(V−32.7)/29.6}+0.015 exp{(V−32.7)/5064.6}

Appendix 2: definition of symbols

I _HERG: HERG current (nA)

G _HERG: maximum conductance of HERG channels expressed in a CHO cell (μS)

m, h: activation and inactivation gates of HERG, respectively

α_m and β_m: opening and closing rate constants, respectively, of activation gate (ms⁻¹)

α_h and β_h: opening and closing rate constants, respectively, of inactivation gate (ms⁻¹)

V: membrane potential (mV)

E _K: reversal potential of K⁺ (mV)