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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 |
| Institution: | Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK. |
| 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. |
| 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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