ArticleJournal of molecular and cellular cardiology2014
CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 81 citations in OpenAlex.
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- Stress-Induced calcium mishandling in cardiac (Patho)physiology.Cellular and molecular life sciences : CMLS · 2025Review
- Piezo1 in heart failure: A new perspective from cytomechanical sensing to diverse cellular pathways.Molecular biology reports · 2025Review
- Alternative Splicing of Serum Response Factor Reveals Isoform-Specific Remodeling in Cardiac Diseases.Genes · 2025Article
- Ca2+/calmodulin-dependent kinase IIδC-induced chronic heart failure does not depend on sarcoplasmic reticulum Ca2+ leak.ESC heart failure · 2024Article
- Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction.Journal of translational medicine · 2024Review
- Biosafe cerium oxide nanozymes protect human pluripotent stem cells and cardiomyocytes from oxidative stress.Journal of nanobiotechnology · 2024Article
- CaMK II in Cardiovascular Diseases, Especially CaMK II-δ: Friends or Enemies.Drug design, development and therapy · 2024Review
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
- Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with CaResearch (Washington, D.C.) · 2023Article
- The role of junctophilin proteins in cellular function.Physiological reviews · 2022Review
- The interplay between cardiac dyads and mitochondria regulated the calcium handling in cardiomyocytes.Frontiers in physiology · 2022Review
- CaPflugers Archiv : European journal of physiology · 2022Review
- The Ryanodine Receptor as a Sensor for Intracellular Environments in Muscles.International journal of molecular sciences · 2021Review
- Integrated Quantitative Phosphoproteomics and Cell-based Functional Screening Reveals Specific Pathological Cardiac Hypertrophy-related Phosphorylation Sites.Molecules and cells · 2021Article
- Article
- CaMKIIδ Splice Variants in the Healthy and Diseased Heart.Frontiers in cell and developmental biology · 2021Review
- Navigating Calcium and Reactive Oxygen Species by Natural Flavones for the Treatment of Heart Failure.Frontiers in pharmacology · 2021Review
- Irisin: A Promising Target for Ischemia-Reperfusion Injury Therapy.Oxidative medicine and cellular longevity · 2021Review
- Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications.Pharmacological research · 2021Review
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Ca(2+)-calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts subjected to global I/R (45/120min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial I/R (1/24h). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A) significantly improved post-ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knock-in mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN (S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca(2+) current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage.
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