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Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
Stephan E Lehnart1, Marco Mongillo, Andrew Bellinger
1Department 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.
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.
Insights
Mutant RyR2 channels cause both seizures and sudden cardiac death by leaking calcium. A new drug (S107) fixed these RyR2 (ryanodine receptor 2) channel defects, preventing seizures and arrhythmias in mice.
Area of Science:
- Neuroscience
- Cardiology
- Molecular Biology
Background:
- Ryanodine receptor 2 (RyR2) is crucial for heart function and also found in the brain.
- Mutations in RyR2 are linked to sudden cardiac death, specifically catecholaminergic polymorphic ventricular tachycardia (CPVT).
- CPVT-associated RyR2 mutations lead to "leaky" channels due to reduced calstabin2 binding.
Purpose of the Study:
- To investigate the role of CPVT-associated RyR2 mutations in neurological and cardiac function.
- To determine if leaky RyR2 channels in the brain can cause seizures independently of cardiac issues.
- To evaluate the therapeutic potential of a novel RyR2-specific compound (S107).
Main Methods:
- Utilized mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice).
- Observed spontaneous and exercise-induced seizures and cardiac arrhythmias.
- Administered S107 to assess its effect on channel function, arrhythmias, and seizure threshold.
Main Results:
- Ryr2-R2474S mice exhibited spontaneous seizures and exercise-induced ventricular arrhythmias, leading to sudden death.
- Treatment with S107 inhibited RyR2 channel leak and prevented cardiac arrhythmias.
- S107 also raised the seizure threshold in the mutant mice, indicating a neurological benefit.
- Leaky RyR2 channels in the brain were shown to cause seizures independent of cardiac arrhythmias.
Conclusions:
- CPVT-associated leaky RyR2-R2474S channels in the brain can induce seizures.
- These findings suggest CPVT is a combined neurocardiac disorder.
- Leaky RyR2 channels contribute to both epilepsy and exercise-induced sudden cardiac death.
