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.