Inhibition of HERG potassium channels by domiphen bromide and didecyl dimethylammonium bromide.
Domiphen bromide and didecyl dimethylammonium bromide were widely used environmental chemicals with potent activity on blockade of human ether-a-go-go related gene (HERG) channels. But the mechanism of their action is not clear. The kinetics of block of HERG channels by domiphen bromide and didecyl dimethylammonium bromide was studied in order to characterize the inhibition of HERG currents by these quaternary ammonium compounds (QACs). Domiphen bromide and didecyl dimethylammonium bromide inhibited HERG channel currents in a dose-dependent manner with IC50 values of 9nM and 5nM, respectively. Block of HERG channel by domiphen bromide and didecyl dimethylammonium bromide was voltage-dependent and use-dependent. Domiphen bromide and didecyl dimethylammonium bromide caused substantial negative shift of the activation curves, accelerated activated process, but had no effects on the deactivation and reactivation processes. The docking models implied that these two compounds bound to PAS domain of HERG channels and inhibited its function. Our data demonstrated that domiphen bromide and didecyl dimethylammonium bromide blocked the HERG channel with a preference for the activated channel state.
Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Kaiyuan Road 190, Guangzhou Science Park, Guangzhou 510530, China.
Yan
Y
Long
The School of Life Sciences, Anhui University, Hefei 230027, China.
Wanjuan
W
Chen
Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Kaiyuan Road 190, Guangzhou Science Park, Guangzhou 510530, China.
Zuoxian
Z
Lin
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
Hongmao
H
Sun
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
Menghang
M
Xia
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
Wei
W
Zheng
Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Kaiyuan Road 190, Guangzhou Science Park, Guangzhou 510530, China. Electronic address: li_zhiyuan@gibh.ac.cn.
Zhiyuan
Z
Li
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology*
D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; C007556:domiphen; C027118:didecyldimethylammonium
Didecyl dimethylammonium bromide (PubChem CID: 16957); Domiphen bromide (PubChem CID: 10866); HERG channel; Patch clamp; Quaternary ammonium compounds