Enhancement of HERG K+ currents by Cd2+ destabilization of the inactivated state

We have studied the functional effects of extracellular Cd2+ on human ether-a-go-go-related gene (HERG) encoded K+ channels, Low concentrations (10-200 mu M) of extracellular Cd2+ increased outward currents through HERG channels; 200 mu M Cd2+ more than doubled HERG currents and altered current kinetics. Cd2+ concentrations up to 200 mu M did not change the voltage dependence of channel activation, but shifted the voltage dependence of inactivation to more depolarized membrane potentials. Cd2+ concentrations greater than or equal to 500 mu M shifted the voltage dependence of channel activation to more positive potentials. These results are consistent with a somewhat specific ability of Cd2+ to destabilize the inactivated state. We tested the hypothesis that channel inactivation is essential for Cd2+-induced increases in HERG KC currents, using a double point mutation (G628C/S631C) that diminishes HERG inactivation (Smith, P. L., T. Baukrowitz, and G. Yellen, 1996, Nature (Lond.). 379:833-836), This inactivation-removed mutant is insensitive to low concentrations of Cd2+. Thus, Cd2+ had two distinct effects on HERG K+ channels. Low concentrations of Cd2+ caused relatively selective effects on inactivation, resulting in a reduction of the apparent rectification of the channel and thereby increasing HERG K+ currents. Higher Cd2+ concentrations affected activation gating as well, possibly by a surface charge screening mechanism or by association with a lower affinity site.