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2. Flecainide Specifically Targets the Monovalent Countercurrent Through the Cardiac Ryanodine Receptor, While a Dominant Opposing Ca 2+ /Ba 2+ Current Is Present.

Author

Gaburjakova, Jana, Domsicova, Michaela, Poturnayova, Alexandra, and Gaburjakova, Marta

Subjects
CALCIUM ions, RYANODINE receptors, VENTRICULAR tachycardia, GAIN-of-function mutations, SARCOPLASMIC reticulum
Abstract

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 Ca2+ 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 Ca2+ 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 Ca2+/Ba2+ 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. [ABSTRACT FROM AUTHOR]

Published
2025
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32. Eu3+detects two functionally distinct luminal Ca2+binding sites in the cardiac- and skeletal muscle ryanodine receptor

Author

Magyar, Zsuzsanna É., Bauer, Jacob, Bauerová-Hlinková, Vladena, Jóna, István, Gaburjakova, Jana, Gaburjakova, Marta, and Almássy, János

Abstract

Ryanodine receptors (RyR) are Ca2+release channels, gated by Ca2+in the cytosol and the sarcoplasmic reticulum lumen. Their regulation is impaired in certain cardiac and muscle diseases. Although a lot of data is available on the luminal Ca2+regulation of RyR, its interpretation is complicated by the possibility that the divalent ions used to probe the luminal binding sites may contaminate the cytoplasmic sites by crossing the channel pore. In this study, we used Eu3+, an impermeable agonist of Ca2+binding sites, as a probe to avoid this complication and to gain more specific information about the function of the luminal Ca2+sensor. Single-channel currents were measured from skeletal muscle and cardiac RyRs (RyR1 and RyR2) using the lipid bilayer technique. We show that RyR2 is activated by the luminal addition of Ca2+while RyR1 is inhibited. These results were qualitatively reproducible using Eu3+. The luminal regulation of RyR1 carrying a mutation associated with malignant hyperthermia was not different from that of the wild-type.

Published
2023
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