Biophys J, November 1999, p. 2534-2541, Vol. 77, No. 5

Enhancement of HERG K⁺ Currents by Cd²⁺ Destabilization of the Inactivated State

Departments of  ^*Pharmacology and  ^#Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602 USA

We have studied the functional effects of extracellular Cd²⁺ on human ether-à-go-go-related gene (HERG) encoded K⁺ channels. Low concentrations (10-200 µM) of extracellular Cd²⁺ increased outward currents through HERG channels; 200 µM Cd²⁺ more than doubled HERG currents and altered current kinetics. Cd²⁺ concentrations up to 200 µM did not change the voltage dependence of channel activation, but shifted the voltage dependence of inactivation to more depolarized membrane potentials. Cd²⁺ concentrations 500 µM 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 K⁺ 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.

Biophys J, November 1999, p. 2534-2541, Vol. 77, No. 5
© 1999 by the Biophysical Society   0006-3495/99/11/2534/08  $2.00

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