Flecainide Specifically Targets the Monovalent Countercurrent Through the Cardiac Ryanodine Receptor, While a Dominant Opposing Ca/Ba Current Is Present.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl channels under cell-like conditions. Particularly, the Tris countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca/Ba current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent.