title: Kinetic model for NS1643 drug activation of WT and L529I variants of Kv11.1 (hERG1) potassium channel.
abstract: Congenital and acquired (drug-induced) forms of the human long-QT syndrome are associated with alterations in Kv11.1 (hERG) channel-controlled repolarizing IKr currents of cardiac action potentials. A mandatory drug screen implemented by many countries led to a discovery of a large group of small molecules that can activate hERG currents and thus may act as potent antiarrhythmic agents. Despite significant progress in identification of channel activators, little is known about their mechanism of action. A combination of electrophysiological studies with molecular and kinetic modeling was used to examine the mechanism of a model activator (NS1643) action on the hERG channel and its L529I mutant. The L529I mutant has gating dynamics similar to that of wild-type while its response to application of NS1643 is markedly different. We propose a mechanism compatible with experiments in which the model activator binds to the closed (C3) and open states (O). We suggest that NS1643 is affecting early gating transitions, probably during movements of the voltage sensor that precede the opening of the activation gate.
authors: Centre for Molecular Modeling, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Laura L
authors: LL
authors: Perissinotti
authors: Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Jiqing
authors: J
authors: Guo
authors: Centre for Molecular Modeling, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Pablo M
authors: PM
authors: De Biase
authors: Department of Pharmacology, University of California at Davis, Davis, California. Electronic address: ceclancy@ucdavis.edu.
authors: Colleen E
authors: CE
authors: Clancy
authors: Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address: hduff@ucalgary.ca.
authors: Henry J
authors: HJ
authors: Duff
authors: Centre for Molecular Modeling, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada. Electronic address: snoskov@ucalgary.ca.
authors: Sergei Y
authors: SY
authors: Noskov
mesh_terms: D002460:Cell Line; D003408:Cresols / Q000494:pharmacology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology*; D014162:Transfection
chemical_list: D003408:Cresols; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D049990:Membrane Transport Modulators; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea