Referenced in: none

Automatically associated channels: Kv11.1

Title: Inhibition of the HERG K+ channel by the antifungal drug ketoconazole depends on channel gating and involves the S6 residue F656.

Authors: John M Ridley, James T Milnes, Rona S Duncan, Mark J McPate, Andrew F James, Harry J Witchel, Jules C Hancox

Journal, date & volume: FEBS Lett., 2006 Apr 3 , 580, 1999-2005

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16542653

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.