Kinetic model for NS1643 drug activation of WT and L529I variants of Kv11.1 (hERG1) potassium channel

Laura L. Perissinotti, Jiqing Guo, Pablo M. De Biase, Colleen E Clancy, Henry J. Duff, Sergei Y. Noskov

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1414-1424
Number of pages11
JournalBiophysical Journal
Volume108
Issue number6
DOIs
StatePublished - Mar 24 2015

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Potassium Channels
Long QT Syndrome
Pharmaceutical Preparations
Action Potentials
Metabolic Activation
1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea

ASJC Scopus subject areas

  • Biophysics

Cite this

Kinetic model for NS1643 drug activation of WT and L529I variants of Kv11.1 (hERG1) potassium channel. / Perissinotti, Laura L.; Guo, Jiqing; De Biase, Pablo M.; Clancy, Colleen E; Duff, Henry J.; Noskov, Sergei Y.

In: Biophysical Journal, Vol. 108, No. 6, 24.03.2015, p. 1414-1424.

Research output: Contribution to journalArticle

Perissinotti, Laura L. ; Guo, Jiqing ; De Biase, Pablo M. ; Clancy, Colleen E ; Duff, Henry J. ; Noskov, Sergei Y. / Kinetic model for NS1643 drug activation of WT and L529I variants of Kv11.1 (hERG1) potassium channel. In: Biophysical Journal. 2015 ; Vol. 108, No. 6. pp. 1414-1424.
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