| Title | Leaky Ca release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. | | Author(s) | Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR | | Institution | Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, and Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, USA. The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA. School of Nursing and Department of Physiology, University of Maryland, Baltimore, Maryland, USA. Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland, USA. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. | | Source | J Clin Invest 2008 Jun 2; 118(6):2230-2245. | | Abstract | The Ca(2+) 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18483626 |
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