ArticleCardiovascular research2009
Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts.
Article in Cardiovascular research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 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
37 citing papers in PubMed, 88 citations in OpenAlex.
- Electrophysiological Mechanisms and Therapeutic Potential of Calcium Channels in Atrial Fibrillation.Reviews in cardiovascular medicine · 2025Review
- Characterization of N-terminal RYR2 variants outside CPVT1 hotspot regions using patient iPSCs reveal pathogenesis and therapeutic potential.Stem cell reports · 2022Article
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).Frontiers in physiology · 2022Article
- Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM.Nature communications · 2021Article
- Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling.Communications biology · 2020Article
- Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.Expert opinion on therapeutic targets · 2020Review
- Tetracaine derivatives for catecholaminergic polymorphic ventricular tachycardia: New drugs for correction of diastolic CaHeart rhythm · 2018Article
- Ryanodine Receptor Structure and Function in Health and Disease.Sub-cellular biochemistry · 2018Review
- Physiology and pathophysiology of excitation-contraction coupling: the functional role of ryanodine receptor.Journal of muscle research and cell motility · 2017Review
- The N-Terminal Region of the Ryanodine Receptor Affects Channel Activation.Frontiers in physiology · 2017Article
- Article
- RyR2 QQ2958 Genotype and Risk of Malignant Ventricular Arrhythmias.Cardiology research and practice · 2016Article
- Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition ameliorates arrhythmias elicited by junctin ablation under stress conditions.Heart rhythm · 2015Article
- FRET-based trilateration of probes bound within functional ryanodine receptors.Biophysical journal · 2014Article
- Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias.Acta crystallographica. Section D, Biological crystallography · 2014Article
- Integrins protect cardiomyocytes from ischemia/reperfusion injury.The Journal of clinical investigation · 2013Article
- Regulation of the cardiac sodium/bicarbonate cotransporter by angiotensin II: potential Contribution to structural, ionic and electrophysiological myocardial remodelling.Current cardiology reviews · 2013Review
- In cardiomyocytes, binding of unzipping peptide activates ryanodine receptor 2 and reciprocally inhibits calmodulin binding.Circulation research · 2013Article
- Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts.Cardiovascular research · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
aimsA domain peptide (DP) matching the Gly(2460)-Pro(2495) region of the cardiac type-2 ryanodine receptor (RyR2), DPc10, is known to mimic channel dysfunction associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), owing to its interference in a normal interaction of the N-terminal (1-600) and central (2000-2500) domains (viz. domain unzipping). Using DPc10 and two other DPs harboring different mutation sites, we investigated the underlying mechanism of abnormal Ca(2+) cycling in failing hearts. METHODS AND
resultsSarcoplasmic reticulum (SR) vesicles and cardiomyocytes were isolated from dog left ventricular muscles for Ca(2+) leak and spark assays. The RyR2 moiety of the SR was fluorescently labelled with methylcoumarin acetate (MCA) using DPs corresponding to the 163-195 and 4090-4123 regions of RyR2 (DP163-195 and DP4090-4123, respectively) as site-directed carriers. Both DPs mediated a specific MCA fluorescence labelling of RyR2. Addition of either DP to the MCA-labelled SR induced domain unzipping, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. Both SR Ca(2+) leak and Ca(2+) spark frequency (SpF) were markedly increased in failing cardiomyocytes. Upon introduction of DP163-195 or DP4090-4123 into normal SR or cardiomyocytes, both Ca(2+) leak and SpF increased to the levels comparable with those of failing myocytes. K201 (JTV519) suppressed all of the effects induced by DP163-195 (domain unzipping and increased Ca(2+) leak and SpF) or those in failing cardiomyocytes, but did not suppress the effects induced by DP4090-4123.
conclusionDefective inter-domain interaction between N-terminal and central domains induces diastolic Ca(2+) leak, leading to heart failure and lethal arrhythmia. Mutation at the C-terminal region seen in CPVT does not seem to communicate with the aforementioned N-terminal and central inter-domain interaction, although spontaneous Ca(2+) leak is similarly induced.
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.