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• W2009050401 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." @default.
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• W2009050401 date "2015-03-01" @default.
• W2009050401 modified "2023-10-17" @default.
• W2009050401 title "Kinetic Model for NS1643 Drug Activation of WT and L529I Variants of Kv11.1 (hERG1) Potassium Channel" @default.
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• W2009050401 doi "https://doi.org/10.1016/j.bpj.2014.12.056" @default.
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