| First Author | Goddard CA | Year | 2008 |
| Journal | Acta Physiol (Oxf) | Volume | 194 |
| Issue | 2 | Pages | 123-40 |
| PubMed ID | 18419777 | Mgi Jnum | J:186379 |
| Mgi Id | MGI:5432112 | Doi | 10.1111/j.1748-1716.2008.01865.x |
| Citation | Goddard CA, et al. (2008) Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts. Acta Physiol (Oxf) 194(2):123-40 |
| abstractText | 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 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). RESULTS: Evoked Ca2+ 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 nm 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 Ca2+ homeostasis and arrhythmogenic properties resembling CPVT with greater effects in the homozygote than the heterozygote demonstrating an important gene dosage effect. |
