title: Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.
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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.forename: Andrew
authors.initials: A
authors.lastname: Bellinger
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lindegger
authors.forename: Bi-Xing
authors.initials: BX
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Hsueh
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Anetta
authors.initials: A
authors.lastname: Wronska
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Drew
authors.forename: Chris W
authors.initials: CW
authors.lastname: Ward
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.forename: Gregory
authors.initials: G
authors.lastname: Morley
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse