ArticleAmerican journal of physiology. Heart and circulatory physiology2014
Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice.
Article in American journal of physiology. Heart and circulatory physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 27 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- T-World Virtual Human Cardiomyocyte. I. Development, Validation, and Cell Arrhythmogenesis.Circulation research · 2026Article
- JP2 and JCN Crosstalk Abrogate MURF1-Mediated JCN Ubiquitination and Degradation in Cardiomyocytes.JACC. Basic to translational science · 2026Article
- Understanding molecular mechanisms driving cadmium-induced mitochondrial dysfunction in human metabolic liver disease.Environmental toxicology and pharmacology · 2026Review
- Reassessment of mechanical restitution in guinea pig cardiomyocytes through refined computational modelling.Scientific reports · 2025Article
- Functional analysis of JPH2-knockout cardiomyocytes identifies ECCD as a novel indicator in a human cardiac modelJPH2.Stem cell research & therapy · 2025Article
- Augmenting workload drives T-tubule assembly in developing cardiomyocytes.The Journal of physiology · 2024Article
- Structure, Function, and Regulation of the Junctophilin Family.Annual review of physiology · 2024Review
- Ion channel trafficking implications in heart failure.Frontiers in cardiovascular medicine · 2024Review
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
- Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade.JACC. Basic to translational science · 2023Article
- Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.Circulation. Arrhythmia and electrophysiology · 2023Article
- The role of junctophilin proteins in cellular function.Physiological reviews · 2022Review
- Study on diverse pathological characteristics of heart failure in different stages based on proteomics.Journal of cellular and molecular medicine · 2022Article
- Understanding the molecular basis of cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2022Review
- The function and regulation of calsequestrin-2: implications in calcium-mediated arrhythmias.Biophysical reviews · 2022Review
- Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels.Frontiers in physiology · 2021Review
- The Physiology and Pathophysiology of T-Tubules in the Heart.Frontiers in physiology · 2021Review
- Junctophilins: Key Membrane Tethers in Muscles and Neurons.Frontiers in molecular neuroscience · 2021Review
- A junctophilin-caveolin interaction enables efficient coupling between ryanodine receptors and BKThe Journal of biological chemistry · 2019Article
- Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity.JCI insight · 2019Article
Corrections and comments
- Erratum issuedCorrigendum.2018
Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca(2+) leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca(2+) release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca(2+) imaging. MCM-shJPH2 cardiomyocytes exhibited an increased spark frequency width with altered spark morphology, which caused increased SR Ca(2+) leakage. Single channel studies identified an increased RyR2 open probability in MCM-shJPH2 mice. The increase in spark frequency and width was observed only in MCM-shJPH2 and not found in mice with increased RyR2 open probability with native JPH2 expression. Na(+)/Ca(2+)-exchanger (NCX) activity was reduced by 50% in MCM-shJPH2 with no detectable change in NCX expression. Additionally, 50% inhibition of NCX through Cd(2+) administration alone was sufficient to increase spark width in myocytes obtained from wild-type mice. Additionally, superresolution analysis of RyR2 and NCX colocalization showed a reduced overlap between RyR2 and NCX in MCM-shJPH2 mice. In conclusion, decreased JPH2 expression causes increased SR Ca(2+) leakage by directly increasing open probability of RyR2 and by indirectly reducing junctional NCX activity through increased dyadic cleft Ca(2+). This demonstrates two novel and independent cellular mechanisms by which JPH2 regulates RyR2-mediated SR Ca(2+) leak and heart failure development.
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Registered trials
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