Inhibition of the HERG K+ channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656 |
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Authors: | Ridley John M Milnes James T Duncan Rona S McPate Mark J James Andrew F Witchel Harry J Hancox Jules C |
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Affiliation: | Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. |
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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 1.7 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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Keywords: | ANOVA, analysis of variance C.I., 95% confidence intervals HEK, human embryonic kidney HERG, human ether-à-go-go-related gene IC50, half-maximal inhibitory drug concentration IHERG, current mediated by the HERG channel IKr, rapid delayed rectifier current KETO, ketoconazole [K+]e, external potassium concentration nH, Hill coefficient t1/2, time taken for the tail current to decline to half of its peak value WT, wild type |
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