ArticleCirculation research2013
In cardiomyocytes, binding of unzipping peptide activates ryanodine receptor 2 and reciprocally inhibits calmodulin binding.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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Who cites it
21 citing papers in PubMed, 40 citations in OpenAlex.
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Gain-of-Function and Loss-of-Function Mutations in the RyR2-Expressing Gene Are Responsible for the CPVT1-Related Arrhythmogenic Activities in the Heart.Current issues in molecular biology · 2024Article
- RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET.ACS chemical biology · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.International journal of molecular sciences · 2023Article
- RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease.Journal of molecular and cellular cardiology · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.bioRxiv : the preprint server for biology · 2023Article
- Synergistic FRET assays for drug discovery targeting RyR2 channels.Journal of molecular and cellular cardiology · 2022Article
- Article
- Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling.Communications biology · 2020Article
- Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure.ACS pharmacology & translational science · 2020Review
- Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia.JCI insight · 2019Article
- Calmodulin inhibition of human RyR2 channels requires phosphorylation of RyR2-S2808 or RyR2-S2814.Journal of molecular and cellular cardiology · 2019Article
- Calmodulinopathy: Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes.Frontiers in cardiovascular medicine · 2018Review
- The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis.The Journal of general physiology · 2017Review
- High-Throughput Screens to Discover Small-Molecule Modulators of Ryanodine Receptor Calcium Release Channels.SLAS discovery : advancing life sciences R & D · 2017Article
- CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift.Journal of molecular and cellular cardiology · 2016Article
- Arrhythmogenic Calmodulin Mutations Affect the Activation and Termination of Cardiac Ryanodine Receptor-mediated Ca2+ Release.The Journal of biological chemistry · 2015Article
- Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity.Journal of molecular and cellular cardiology · 2015Article
- FRET-based trilateration of probes bound within functional ryanodine receptors.Biophysical journal · 2014Article
- Cardiac myocyte Z-line calmodulin is mainly RyR2-bound, and reduction is arrhythmogenic and occurs in heart failure.Circulation research · 2014Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
rationaleOne hypothesis for elevated Ca(2+) leak through cardiac ryanodine receptors (ryanodine receptor 2 [RyR2]) in heart failure is interdomain unzipping that can enhance aberrant channel activation. A peptide (domain peptide corresponding to RyR2 residues 2460-2495 [DPc10]) corresponding to RyR2 central domain residues 2460-2495 recapitulates this arrhythmogenic RyR2 leakiness by unzipping N-terminal and central domains. Calmodulin (CaM) and FK506-binding protein (FKBP12.6) bind to RyR2 and stabilize the closed channel. Little is known about DPc10 binding to the RyR2 and how that may interact with binding (and effects) of CaM and FKBP12.6 to RyR2.
objectiveTo measure, directly in cardiac myocytes, the kinetics and binding affinity of DPc10 to RyR2 and how that affects RyR2 interaction with FKBP12.6 and CaM. METHODS AND
resultsWe used permeabilized rat ventricular myocytes and fluorescently labeled DPc10, FKBP12.6, and CaM. DPc10 access to its binding site is extremely slow in resting RyR2 but is accelerated by promoting RyR opening or unzipping (by unlabeled DPc10). RyR2-bound CaM (but not FKBP12.6) drastically slowed DPc10 binding. Conversely, DPc10 binding significantly reduced CaM (but not FKBP12.6) binding to the RyR2. Fluorescence resonance energy transfer measurements indicate that DPc10-binding and CaM-binding sites are separate and allow triangulation of the structural DPc10 binding locus on RyR2 vs FKBP12.6-binding and CaM-binding sites.
conclusionsDPc10-RyR2 binding is sterically limited by the resting zipped RyR2 state. CaM binding to RyR2 stabilizes this zipped state, whereas RyR2 activation or prebound DPc10 enhances DPc10 access. DPc10-binding and CaM-binding sites are distinct but are allosterically interacting RyR2 sites. Neither DPc10 nor FKBP12.6 influences RyR2 binding of the other.
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