Inhibition of the HERG K+channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656
- 7 March 2006
- journal article
- Published by Wiley in FEBS Letters
- Vol. 580 (8), 1999-2005
- https://doi.org/10.1016/j.febslet.2006.02.073
Abstract
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 1.7μM. 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 ∼4-fold and ∼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 bindingKeywords
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