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Monday 03 April 2006

Inhibition of the HERG K+ channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656.

By: Ridley JM, Milnes JT, Duncan RS, McPate MJ, James AF, Witchel HJ, Hancox JC.

FEBS Lett 2006 Apr 3;580(8):1999-2005

The mechanism of human ether-a-go-go-related gene (HERG) K+ channel blockade by the antifungal agent ketoconazole was investigated using patch-clamp recording from mammalian cell lines. Ketoconazole inhibited whole-cell HERG current (IHERG) with a clinically relevant half-maximal inhibitory drug concentration (IC50) value of 1.7 microM. The voltage- and time-dependent characteristics of IHERG blockade by ketoconazole indicated dependence of block on channel gating, ruling out a significant role for closed-state channel inhibition. The S6 HERG mutations Y652A and F656A produced approximately 4-fold and approximately 21-fold increases in IC50 for IHERG blockade, respectively. Thus, ketoconazole accesses the HERG channel pore-cavity on channel gating, and the S6 residue F656 is an important determinant of ketoconazole binding.

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