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Does ketoconazole inhibit HERG K+ channels through a mechanism dependent on channel gating and specific S6 residues in mammalian cell lines?
Does ketoconazole inhibit HERG K+ channels through a mechanism dependent on channel gating and specific S6 residues in mammalian cell lines?
Ketoconazole inhibits HERG K+ channels via a mechanism dependent on channel gating, with the S6 residue F656 playing a critical role in drug binding.
Supports gating-dependent HERG blockade by ketoconazole; leaves open relevance to human cardiotoxicity.
The mechanism of human ether-à-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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Ridley et al. (2006) studied this question.
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