ArticleThe Journal of physiology2014
Genetic ablation of ryanodine receptor 2 phosphorylation at Ser-2808 aggravates Ca(2+)-dependent cardiomyopathy by exacerbating diastolic Ca2+ release.
Article in The Journal of physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed, 30 citations in OpenAlex.
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- A perspective on the future of heart failure research.Journal of molecular and cellular cardiology plus · 2026Article
- Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.Journal of molecular and cellular cardiology plus · 2024Article
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- MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.International journal of molecular sciences · 2022Article
- Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.Journal of cellular and molecular medicine · 2021Article
- TRIC-A regulates intracellular CaPflugers Archiv : European journal of physiology · 2021Review
- Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K-AKT-nNOS signaling.The Journal of biological chemistry · 2020Article
- Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS.Basic research in cardiology · 2020Article
- Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias.International journal of molecular sciences · 2020Article
- Disruption of CaCirculation · 2019Article
- Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.Journal of the American Heart Association · 2018Article
- The effect of PKA-mediated phosphorylation of ryanodine receptor on SR CaJournal of molecular and cellular cardiology · 2017Article
- Ablation of the cardiac ryanodine receptor phospho-site Ser2808 does not alter the adrenergic response or the progression to heart failure in mice. Elimination of the genetic background as critical variable.Journal of molecular and cellular cardiology · 2017Article
- Regulation of sarcoplasmic reticulum CaJournal of molecular and cellular cardiology · 2016Review
- Neuronal NaJACC. Basic to translational science · 2016Article
- Article
- Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT.Cardiovascular research · 2015Article
- Alternating membrane potential/calcium interplay underlies repetitive focal activity in a genetic model of calcium-dependent atrial arrhythmias.The Journal of physiology · 2015Article
- Maximal acceleration of Ca2+ release refractoriness by β-adrenergic stimulation requires dual activation of kinases PKA and CaMKII in mouse ventricular myocytes.The Journal of physiology · 2015Article
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8 authors at 3 institutions in 1 country.
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Abstract
Phosphorylation of the cardiac ryanodine receptor (RyR2) by protein kinase A (PKA) at Ser-2808 is suggested to mediate the physiological 'fight or flight' response and contribute to heart failure by rendering the sarcoplasmic reticulum (SR) leaky for Ca(2+). In the present study, we examined the potential role of RyR2 phosphorylation at Ser-2808 in the progression of Ca(2+)-dependent cardiomyopathy (CCM) by using mice genetically modified to feature elevated SR Ca(2+) leak while expressing RyR2s that cannot be phosphorylated at this site (S2808A). Surprisingly, rather than alleviating the disease phenotype, constitutive dephosphorylation of Ser-2808 aggravated CCM as manifested by shortened survival, deteriorated in vivo cardiac function, exacerbated SR Ca(2+) leak and mitochondrial injury. Notably, the deteriorations of cardiac function, myocyte Ca(2+) handling, and mitochondria integrity were consistently worse in mice with heterozygous ablation of Ser-2808 than in mice with complete ablation. Wild-type (WT) and CCM myocytes expressing unmutated RyR2s exhibited a high level of baseline phosphorylation at Ser-2808. Exposure of these CCM cells to protein phosphatase 1 caused a transitory increase in Ca(2+) leak attributable to partial dephosphorylation of RyR2 tetramers at Ser-2808 from more fully phosphorylated state. Thus, exacerbated Ca(2+) leak through partially dephosphorylated RyR2s accounts for the prevalence of the disease phenotype in the heterozygous S2808A CCM mice. These results do not support the importance of RyR2 hyperphosphorylation in Ca(2+)-dependent heart disease, and rather suggest roles for the opposite process, the RyR2 dephosphorylation at this residue in physiological and pathophysiological Ca(2+) signalling.
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