Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts

Goddard, C. A., Ghais, N. S., Zhang, Y., Williams, Alan John, Colledge, W. H., Grace, A. A. and Huang, C. L.-H. 2008. Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts. Acta Physiologica 194 (2) , pp. 123-140. 10.1111/j.1748-1716.2008.01865.x

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Abstract

Aim:  To explore the physiological consequences of the ryanodine receptor (RyR2)-P2328S mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods:  We 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). Results:  Evoked 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. 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	cardiac action potentials; cardiac arrhythmogenesis; catecholaminergic polymorphic ventricular tachycardia; genetically modified mice; ryanodine receptor; P2328S-RyR2
ISSN:	1748-1708
Related URLs:	Publisher
Last Modified:	12 Jun 2019 02:29
URI:	https://orca.cardiff.ac.uk/id/eprint/45123

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