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Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
- Source :
- Journal of Clinical Investigation.
- Publication Year :
- 2008
- Publisher :
- American Society for Clinical Investigation, 2008.
-
Abstract
- The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in “leaky” RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.
- Subjects :
- Heterozygote
medicine.medical_specialty
Mutation, Missense
Hippocampus
cardiomyocytes
Mice, Transgenic
Biology
Catecholaminergic polymorphic ventricular tachycardia
Models, Biological
Ryanodine receptor 2
Sudden cardiac death
Tacrolimus Binding Proteins
Mice
Epilepsy
Ventricular arrhythmias
Internal medicine
medicine
Animals
Patch clamp
Calcium signaling
Polymorphism, Genetic
Models, Genetic
Seizure threshold
Calcium signalling
Ryanodine Receptor Calcium Release Channel
General Medicine
musculoskeletal system
medicine.disease
Death, Sudden, Cardiac
Mutation
cardiovascular system
Cardiology
tissues
Research Article
Subjects
Details
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....fd787c58f6f67e6e91dfc3f49c970d03
- Full Text :
- https://doi.org/10.1172/jci35346