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Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential
Samantha C Salvage1,2, Esther M Gallant3, James A Fraser1
1Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Abstract:
Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted our explorations of the effects of flecainide on their RyR2 channels. Lipid bilayer electrophysiology techniques demonstrated a novel, paradoxical increase in RyR2 activity. Preceding flecainide exposure, channels were mildly activated by 1 mM luminal Ca2+ and 1 µM cytoplasmic Ca2+, with open probabilities (Po) of 0.03 ± 0.01 (wild type, WT) or 0.096 ± 0.024 (P2328S). Open probability (Po) increased within 0.5 to 3 min of exposure to 0.5 to 5.0 µM cytoplasmic flecainide, then declined with higher concentrations of flecainide. There were no such increases in a subset of high Po channels with Po ≥ 0.08, although Po then declined with ≥5 µM (WT) or ≥50 µM flecainide (P2328S). On average, channels with Po < 0.08 were significantly activated by 0.5 to 10 µM of flecainide (WT) or 0.5 to 50 µM of flecainide (P2328S). These results suggest that flecainide can bind to separate activation and inhibition sites on RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels.
Insights
Flecainide paradoxically increases cardiac ryanodine receptor 2 (RyR2) activity at low concentrations, potentially explaining treatment variability in arrhythmias like catecholaminergic polymorphic ventricular tachycardia (CPVT). Higher concentrations inhibit activity.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Cardiac ryanodine receptor 2 (RyR2) mutations are linked to arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and atrial fibrillation.
- Flecainide is a common treatment for CPVT, but its efficacy varies, suggesting complex interactions with cardiac ion channels.
Purpose of the Study:
- To investigate the direct effects of flecainide on cardiac ryanodine receptor 2 (RyR2) channel activity, particularly in the context of the RyR2-P2328S mutation associated with CPVT.
- To elucidate the concentration-dependent mechanisms underlying flecainide's interaction with RyR2.
Main Methods:
- Utilized lipid bilayer electrophysiology to directly measure the open probability (Po) of purified RyR2 channels.
- Exposed RyR2 channels (wild type and P2328S mutant) to varying concentrations of cytoplasmic flecainide under controlled calcium conditions.
Main Results:
- Flecainide exhibited a biphasic effect on RyR2 activity: low concentrations (0.5-50 µM) paradoxically increased Po in channels with lower baseline activity (Po < 0.08).
- Higher flecainide concentrations (≥5 µM for WT, ≥50 µM for P2328S) inhibited RyR2 channel activity.
- The RyR2-P2328S mutation did not prevent flecainide-induced activation, though sensitivity to inhibition differed.
Conclusions:
- Flecainide can exert both activating and inhibitory effects on RyR2 channels, depending on flecainide concentration and the channel's basal activity state.
- This dual action suggests distinct binding sites for activation and inhibition on RyR2, offering a potential explanation for flecainide's variable clinical efficacy in CPVT and other RyR2-related disorders.
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