RyR2 Channel Activity Determines the Potency of State-Dependent RyR2 Blockers for Suppressing Arrhythmogenic Calcium Waves

Abstract

Mutations in ryanodine receptors (RyR2) or calsequestrin (casq2) cause catecholaminergic- polymorphic ventricular tachycardia (CPVT). We previously reported that the RyR2 open-channel blocker flecainide (FLEC) suppresses Ca2+ waves and prevents CPVT in mice and humans. Here we test the hypothesis that the open-state block by FLEC significantly contributes to FLEC efficacy in CPVT. We reasoned that FLEC would preferentially affect myocytes lacking casq2 (casq2-/-), which have higher rates of spontaneous RyR2 channel openings compared to WT channels. To test this hypothesis, we compared FLEC with tetracaine, a RyR2 channel blocker that has no state dependence and binds equally well to closed RyR2 channels. We found that FLEC reduced the incidence, amplitude and frequency of Ca2+ waves with significantly higher potency in casq2-/- myocytes compared to WT myocytes (Figure). In contrast, tetracaine did not suppress Ca2+ waves and had equal potency in WT and casq2-/- myocytes (Figure). Conclusion: RyR2 channel activity likely determines the potency of open-state RyR2 blockers such as FLEC for suppressing arrhythmogenic Ca2+ waves, a mechanism likely relevant to FLEC antiarrhythmic efficacy in CPVT. NIH HL88635 & HL71670.View Large Image | View Hi-Res Image | Download PowerPoint Slide