Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential Pro-Arrhythmic Action

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 8; p. 2101
• Main Authors: Salvage, Samantha C, Gallant, Esther M, Fraser, James A, Huang, Christopher L-H, Dulhunty, Angela F
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-08-2021; MDPI
• Subjects: Animals; Anti-Arrhythmia Agents - metabolism; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; atrial fibrillation; Calcium; Calcium - metabolism; catecholaminergic polymorphic ventricular tachycardia; Channel opening; Electrophysiology; Fibrillation; flecainide; Flecainide - metabolism; Flecainide - pharmacology; Heart; Incorporation; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Lipid bilayers; Lipid Bilayers - metabolism; Lipids; Membrane Potentials; Mice; Mutation; Physiology; Receptor channels; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; RyR2; RyR2 activation; RyR2-P2328S; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Sodium currents; Tachycardia; Ventricle; Voltage-Gated Sodium Channel Blockers - metabolism; Voltage-Gated Sodium Channel Blockers - pharmacology; Australia; RyR2; RyR2-P2328S; atrial fibrillation; catecholaminergic polymorphic ventricular tachycardia; RyR2 activation; flecainide; RyR2 inhibition
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10082101

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 Ca
and 1 µM cytoplasmic Ca
, with open probabilities (
) of 0.03 ± 0.01 (wild type, WT) or 0.096 ± 0.024 (P2328S). Open probability (
) 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
channels with
≥ 0.08, although
then declined with ≥5 µM (WT) or ≥50 µM flecainide (P2328S). On average, channels with
< 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.