rpr260243 and Arrhythmias--Cardiac

hERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation.

Topics: Arrhythmias, Cardiac; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart; Humans; Piperidines

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity for targeted treatment of LQTS. However, a limiting concern is over-activation of hERG resurgent current during the action potential and abbreviated repolarization. Activators that slow deactivation gating (type I), such as RPR260243, may enhance repolarizing hERG current during the refractory period, thus ameliorating arrhythmogenicity with reduced early repolarization risk. Here, we show that, at physiological temperature, RPR260243 enhances hERG channel repolarizing currents conducted in the refractory period in response to premature depolarizations. This occurs with little effect on the resurgent hERG current during the action potential. The effects of RPR260243 were particularly evident in LQTS2-associated R56Q mutant channels, whereby RPR260243 restored WT-like repolarizing drive in the early refractory period and diastolic interval, combating attenuated protective currents. In silico kinetic modeling of channel gating predicted little effect of the R56Q mutation on hERG current conducted during the action potential and a reduced repolarizing protection against afterdepolarizations in the refractory period and diastolic interval, particularly at higher pacing rates. These simulations predicted partial rescue from the arrhythmic effects of R56Q by RPR260243 without risk of early repolarization. Our findings demonstrate that the pathogenicity of some hERG variants may result from reduced repolarizing protection during the refractory period and diastolic interval with limited effect on action potential duration, and that the hERG channel activator RPR260243 may provide targeted antiarrhythmic potential in these cases.

Topics: Arrhythmias, Cardiac; ERG1 Potassium Channel; Ether; Ether-A-Go-Go Potassium Channels; Humans; Long QT Syndrome; Piperidines; Quinolines

Human ether-à-go-go related gene (hERG) K

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart Rate; Kinetics; Myocytes, Cardiac; Oocytes; Piperidines; Quinolines; Refractory Period, Electrophysiological; Signal Transduction; Xenopus laevis; Zebrafish; Zebrafish Proteins