ArticleJournal of molecular and cellular cardiology2016
CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift.
Article in Journal of molecular and cellular cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 108 citations in OpenAlex.
- Mitochondrial heterogeneity across cardiac cell types in heart failure with preserved ejection fraction.Redox biology · 2026Review
- Exploring the role of CaMKII in exercise-induced cardioprotection.Human cell · 2026Review
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Istaroxime in Acute Heart Failure and Early Cardiogenic Shock: A Calcium-Cycling Approach to Inotropic Therapy.International journal of molecular sciences · 2026Review
- Shengmai San Ameliorates High-Glucose-Induced Calcium Homeostasis Imbalance via Improving Energy Metabolism in Neonatal Rat Cardiomyocytes.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- TRIC-A Loss Sensitizes the Heart to β-Adrenergic Stress and Drives Cardiomyocyte Death and Fibrosis.Biomolecules · 2026Article
- The interaction between sarcoplasmic reticulum and mitochondria: a novel mechanism for cardiac arrhythmia.Frontiers in physiology · 2026Review
- Synergistic antiarrhythmic mechanism of IJournal of translational medicine · 2025Article
- Stress-Induced calcium mishandling in cardiac (Patho)physiology.Cellular and molecular life sciences : CMLS · 2025Review
- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Nuclear CaMKII Isoforms as Regulators of Transcription: From Developmental to Pathological Persistence.Medical sciences (Basel, Switzerland) · 2025Review
- Atrial cardiomyopathy resulting from loss of plakophilin-2 expression: Response to adrenergic stimulation and implications for the exercise response.The Journal of physiology · 2025Article
- The mechanism of secreted frizzled-related protein 1 in alleviating cardiomyocyte injury and heart failure.Frontiers in cardiovascular medicine · 2025Review
- Aging-associated mechanisms of atrial fibrillation progression and their therapeutic potential.The journal of cardiovascular aging · 2024Article
- Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice.International journal of molecular sciences · 2024Article
- Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.Journal of molecular and cellular cardiology · 2024Article
- Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors.Nature communications · 2024Article
- Phosphorylation of RyR2 simultaneously expands the dyad and rearranges the tetramers.The Journal of general physiology · 2024Article
- 1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities.Journal of medicinal chemistry · 2023Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Diastolic calcium (Ca) leak via cardiac ryanodine receptors (RyR2) can cause arrhythmias and heart failure (HF). Ca/calmodulin (CaM)-dependent kinase II (CaMKII) is upregulated and more active in HF, promoting RyR2-mediated Ca leak by RyR2-Ser2814 phosphorylation. Here, we tested a mechanistic hypothesis that RyR2 phosphorylation by CaMKII increases Ca leak by promoting a pathological RyR2 conformation with reduced CaM affinity. Acute CaMKII activation in wild-type RyR2, and phosphomimetic RyR2-S2814D (vs. non-phosphorylatable RyR2-S2814A) knock-in mouse myocytes increased SR Ca leak, reduced CaM-RyR2 affinity, and caused a pathological shift in RyR2 conformation (detected via increased access of the RyR2 structural peptide DPc10). This same trio of effects was seen in myocytes from rabbits with pressure/volume-overload induced HF. Excess CaM quieted leak and restored control conformation, consistent with negative allosteric coupling between CaM affinity and DPc10 accessible conformation. Dantrolene (DAN) also restored CaM affinity, reduced DPc10 access, and suppressed RyR2-mediated Ca leak and ventricular tachycardia in RyR2-S2814D mice. We propose that a common pathological RyR2 conformational state (low CaM affinity, high DPc10 access, and elevated leak) may be caused by CaMKII-dependent phosphorylation, oxidation, and HF. Moreover, DAN (or excess CaM) can shift this pathological gating state back to the normal physiological conformation, a potentially important therapeutic approach.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.