Abstract
AimTo explore the physiological consequences of the ryanodine receptor (RyR2)-P2328S mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT).MethodsWe generated heterozygotic (RyR2p/s) and homozygotic (RyR2s/s) transgenic mice and studied Ca2+ signals from regularly stimulated, Fluo-3-loaded, cardiac myocytes. Results were compared with monophasic action potentials (MAPs) in Langendorff-perfused hearts under both regular and programmed electrical stimulation (PES).ResultsEvoked Ca2+ transients from wild-type (WT), heterozygote (RyR2p/s) and homozygote (RyR2s/s) myocytes had indistinguishable peak amplitudes with RyR2s/s showing subsidiary events. Adding 100 nm isoproterenol produced both ectopic peaks and subsidiary events in WT but not RyR2p/s and ectopic peaks and reduced amplitudes of evoked peaks in RyR2s/s. Regularly stimulated WT, RyR2p/s and RyR2s/s hearts showed indistinguishable MAP durations and refractory periods. RyR2p/s hearts showed non-sustained ventricular tachycardias (nsVTs) only with PES. Both nsVTs and sustained VTs (sVTs) occurred with regular stimuli and PES with isoproterenol treatment. RyR2s/s hearts showed higher incidences of nsVTs before but mainly sVTs after introduction of isoproterenol with both regular stimuli and PES, particularly at higher pacing frequencies. Additionally, intrinsically beating RyR2s/s showed extrasystolic events often followed by spontaneous sVT.ConclusionThe RyR2-P2328S mutation results in marked alterations in cellular Ca2+ homeostasis and arrhythmogenic properties resembling CPVT with greater effects in the homozygote than the heterozygote demonstrating an important gene dosage effect.
Highlights
ventricular tachycardia (VT) occurred with regular stimuli and programmed electrical stimulation (PES) with isoproterenol treatment
It has been suggested that FKBP12.6 binding to RyR2 stabilizes the closed state of the channel during diastole and promotes the coupling of RyR2 subunits enabling channel opening during excitation contraction coupling (Yano et al 2000, 2005a, Bers 2002, Wehrens et al 2004)
A second PCR can be used to confirm the presence of the RyR2P2328S allele
Summary
To explore the physiological consequences of the ryanodine receptor
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