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Physiological consequences of the P2328S mutation in the ryanodine receptor ( RyR2 ) gene in genetically modified murine hearts
Author(s) -
Goddard C. A.,
Ghais N. S.,
Zhang Y.,
Williams A. J.,
Colledge W. H.,
Grace A. A.,
Huang C. L.H.
Publication year - 2008
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2008.01865.x
Subject(s) - ryanodine receptor 2 , catecholaminergic polymorphic ventricular tachycardia , ryanodine receptor , medicine , endocrinology , heterozygote advantage , transgene , biology , chemistry , cardiology , receptor , gene , genetics , allele
Aim: To explore the physiological consequences of the ryanodine receptor (RyR2)‐ P2328S mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods: We generated heterozygotic ( RyR2 p/s ) and homozygotic ( RyR2 s/s ) transgenic mice and studied Ca 2+ 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). Results: Evoked Ca 2+ transients from wild‐type ( WT ), heterozygote ( RyR2 p/s ) and homozygote ( RyR2 s/s ) myocytes had indistinguishable peak amplitudes with RyR2 s/s showing subsidiary events. Adding 100 n m isoproterenol produced both ectopic peaks and subsidiary events in WT but not RyR2 p/s and ectopic peaks and reduced amplitudes of evoked peaks in RyR2 s/s . Regularly stimulated WT , RyR2 p/s and RyR2 s/s hearts showed indistinguishable MAP durations and refractory periods. RyR2 p/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. RyR2 s/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 RyR2 s/s showed extrasystolic events often followed by spontaneous sVT. Conclusion: The RyR2‐P2328S mutation results in marked alterations in cellular Ca 2+ homeostasis and arrhythmogenic properties resembling CPVT with greater effects in the homozygote than the heterozygote demonstrating an important gene dosage effect.