Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
Stephan E. Lehnart, … , Gregory Morley, Andrew R. Marks
Stephan E. Lehnart, … , Gregory Morley, Andrew R. Marks
Published May 15, 2008
Citation Information: J Clin Invest. 2008;118(6):2230-2245. https://doi.org/10.1172/JCI35346.
View: Text | PDF
Research Article Cardiology

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

  • Text
  • PDF
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

Stephan E. Lehnart, Marco Mongillo, Andrew Bellinger, Nicolas Lindegger, Bi-Xing Chen, William Hsueh, Steven Reiken, Anetta Wronska, Liam J. Drew, Chris W. Ward, W.J. Lederer, Robert S. Kass, Gregory Morley, Andrew R. Marks

×

Figure 1

RyR2-homozygous R2474S knock-in mice exhibit increased embryonic lethality that is reduced by a novel RyR2 stabilizing drug (S107) that inhibits Ca2+ leak.

Options: View larger image (or click on image) Download as PowerPoint
RyR2-homozygous R2474S knock-in mice exhibit increased embryonic lethali...
(A) Generation of Ryr2-R2474S knock-in mouse. Top: targeted mutagenesis of mouse RyR2 exon 49; middle: homologous ES cell recombination of the mutant Ryr2-R2474S allele; bottom: Cre-mediated excision of the floxed neo cassette results in Ryr2-R2474S knock-in. (B) Confirmation of homologous recombination of mutant Ryr2-R2474S allele by Southern blot (left); PCR detects mutant R2474S (RS) allele in progeny (right). (C) Lethality of the homozygous Ryr2-R2474S (RS/RS) mice at day 28 after birth as evidenced by significant non-Mendelian inheritance with underrepresentation of the homozygous genotype. (D) Normal embryonic development and cardiac maturation up to day E13.5 as shown by representative histological sections. Original magnification: ×3 (left, longitudinal section), ×5 (right, cross-sections). (E) Rescue of homozygous Ryr2-R2474S embryos by treatment of the pregnant mothers with S107, a small compound that binds specifically to RyR2, enhances calstabin2 binding and inhibits Ca2+ leak from mutant RyR2 channels. Up to day E13.5, there was normal Mendelian inheritance (left). However, embryonic lethality was evidenced by abnormal Mendelian inheritance at day E16.5 (middle), and this was prevented by S107 treatment, which resulted in normal Mendelian inheritance due to improved survival of the homozygous Ryr2-R2474S embryos (right). P values represent statistical comparison of the observed genotypes to expected genotypes based on Mendelian inheritance patterns. Asterisks indicate significant difference between the observed and expected genotype ratios.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts