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Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243
Jacob M Kemp1, Dominic G Whittaker2, Ravichandra Venkateshappa1
1Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, Canada.
The Journal of General Physiology
|August 16, 2021
Summary
hERG channel activators like RPR260243 show therapeutic potential for long QT syndrome type 2 (LQTS2). This study demonstrates RPR260243 enhances cardiac repolarization without increasing arrhythmia risk.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
- Molecular Cardiology
Background:
- Human Ether-à-go-go (hERG) channels are crucial for cardiac repolarization.
- Dysfunctional hERG channels, due to inherited variants or drug block, are linked to long QT syndrome type 2 (LQTS2) and cardiac arrhythmias.
- hERG activators offer a therapeutic strategy for LQTS, but concerns exist regarding over-activation and shortened repolarization.
Purpose of the Study:
- To investigate the therapeutic potential of the hERG activator RPR260243 in targeting LQTS2.
- To evaluate the effects of RPR260243 on hERG channel gating, particularly deactivation kinetics, and its impact on cardiac repolarization and arrhythmogenicity.
- To assess the efficacy of RPR260243 in correcting the functional deficits of LQTS2-associated hERG mutations.
Main Methods:
- Electrophysiological recordings of hERG channel currents at physiological temperature.
- In silico kinetic modeling of hERG channel gating dynamics.
- Assessment of RPR260243 effects on wild-type and R56Q mutant hERG channels in response to premature depolarizations and varying pacing rates.
Main Results:
- RPR260243 enhances hERG repolarizing currents during the refractory period with minimal impact on resurgent current during the action potential.
- The compound effectively restored wild-type-like repolarizing function in LQTS2-associated R56Q mutant channels.
- In silico modeling predicted that RPR260243 could mitigate arrhythmic risks associated with the R56Q mutation without inducing early repolarization issues.
Conclusions:
- Pathogenicity of certain hERG variants may stem from reduced repolarizing protection during the refractory period and diastolic interval.
- The hERG activator RPR260243 demonstrates targeted antiarrhythmic potential for specific LQTS2 cases.
- RPR260243 offers a promising therapeutic avenue for LQTS by selectively enhancing protective repolarizing currents.
