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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
Author(s) -
Ridley John M.,
Milnes James T.,
Duncan Rona S.,
McPate Mark J.,
James Andrew F.,
Witchel Harry J.,
Hancox Jules C.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.02.073
Subject(s) - herg , ketoconazole , gating , chemistry , patch clamp , pharmacology , blockade , ic50 , antifungal , potassium channel , biophysics , biochemistry , in vitro , biology , receptor , microbiology and biotechnology
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 ( I HERG ) with a clinically relevant half‐maximal inhibitory drug concentration (IC 50 ) value of 1.7 μM. The voltage‐ and time‐dependent characteristics of I HERG 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 IC 50 for I HERG 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.