ArticleThe Journal of clinical investigation2010
Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
140 citing papers in PubMed, 228 citations in OpenAlex.
- βNaunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine.World journal of cardiology · 2026Review
- Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts.Journal of molecular and cellular cardiology · 2026Review
- Aberrant myocardial calcium cycling: pathogenic mechanisms and targeted therapeutics for heart failure.Frontiers in cardiovascular medicine · 2026Review
- Ryanodine receptor 2-mediated calcium leak is associated with increased glyoxalase I in the aging brain.JCI insight · 2025Article
- Targeting Calcium Regulation for Heart Failure and Arrhythmia Therapeutics: A Critical Review.Circulation · 2025Review
- The role of A-kinase anchoring proteins in cardiovascular diseases and recent advances.Frontiers in cell and developmental biology · 2025Review
- Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer's disease neuropathology.Frontiers in aging neuroscience · 2025Review
- Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.Journal of molecular and cellular cardiology plus · 2024Article
- Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders.Nature communications · 2024Article
- A dual-targeted drug inhibits cardiac ryanodine receptor CaLife science alliance · 2024Article
- Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems.Circulation. Genomic and precision medicine · 2024Review
- Calmodulin Mutations in Human Disease.Channels (Austin, Tex.) · 2023Review
- Brain Regulation of Cardiac Function during Hypoglycemia.Metabolites · 2023Review
- Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes.Stem cell research & therapy · 2023Article
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
- Changes of calcium cycling in HFrEF and HFpEF.Mechanobiology in medicine · 2023Review
- Heart failure-induced cognitive dysfunction is mediated by intracellular CaNature neuroscience · 2023Article
- Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.International journal of molecular sciences · 2023Article
80 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this leak is an emerging therapeutic strategy. To explore the role of chronic PKA phosphorylation of RyR2 in HF pathogenesis and treatment, we generated a knockin mouse with aspartic acid replacing serine 2808 (mice are referred to herein as RyR2-S2808D+/+ mice). This mutation mimics constitutive PKA hyperphosphorylation of RyR2, which causes depletion of the stabilizing subunit FKBP12.6 (also known as calstabin2), resulting in leaky RyR2. RyR2-S2808D+/+ mice developed age-dependent cardiomyopathy, elevated RyR2 oxidation and nitrosylation, reduced SR Ca2+ store content, and increased diastolic SR Ca2+ leak. After myocardial infarction, RyR2-S2808D+/+ mice exhibited increased mortality compared with WT littermates. Treatment with S107, a 1,4-benzothiazepine derivative that stabilizes RyR2-calstabin2 interactions, inhibited the RyR2-mediated diastolic SR Ca2+ leak and reduced HF progression in WT and RyR2-S2808D+/+ mice. In contrast, β-adrenergic receptor blockers improved cardiac function in WT but not in RyR2-S2808D+/+ mice.Thus, chronic PKA hyperphosphorylation of RyR2 results in a diastolic leak that causes cardiac dysfunction. Reversing PKA hyperphosphorylation of RyR2 is an important mechanism underlying the therapeutic action of β-blocker therapy in HF.
Indexed as
Identifiers
What OpenQuestion holds
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.