ArticleCirculation research2014
Cardiac myocyte Z-line calmodulin is mainly RyR2-bound, and reduction is arrhythmogenic and occurs in heart failure.
Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 80 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
- Dynamic-Structure Redesign of Calmodulin Reveals Mechanistic Constraints on Ryr2 Regulation.bioRxiv : the preprint server for biology · 2026Article
- Calmodulin D133H Disrupts CaCells · 2025Article
- Excitation and mechanical contraction of a 3D cardiomyocyte model.Biophysical journal · 2025Article
- Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors.Nature communications · 2024Article
- The Dysfunction of CaInternational journal of molecular sciences · 2023Review
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.International journal of molecular sciences · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.bioRxiv : the preprint server for biology · 2023Article
- Role of CaArchives of toxicology · 2023Review
- CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms.Journal of cell science · 2022Article
- CaMKIIδ post-translational modifications increase affinity for calmodulin inside cardiac ventricular myocytes.Journal of molecular and cellular cardiology · 2021Article
- Mechanistic link between CaM-RyR2 interactions and the genesis of cardiac arrhythmia.Biophysical journal · 2021Article
- CaThe Journal of biological chemistry · 2020Article
- The functional significance of redox-mediated intersubunit cross-linking in regulation of human type 2 ryanodine receptor.Redox biology · 2020Article
- Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from theInternational journal of molecular sciences · 2020Article
- Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy: A Translational Perspective.Circulation research · 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
- Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality.Cardiovascular research · 2019Article
- Role of circular RNAs in cardiovascular diseases.Experimental biology and medicine (Maywood, N.J.) · 2019Review
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
rationaleCalmodulin (CaM) associates with cardiac ryanodine receptor type-2 (RyR2) as an important regulator. Defective CaM-RyR2 interaction may occur in heart failure, cardiac hypertrophy, and catecholaminergic polymorphic ventricular tachycardia. However, the in situ binding properties for CaM-RyR2 are unknown.
objectiveWe sought to measure the in situ binding affinity and kinetics for CaM-RyR2 in normal and heart failure ventricular myocytes, estimate the percentage of Z-line-localized CaM that is RyR2-bound, and test cellular function of defective CaM-RyR2 interaction. METHODS AND
resultsUsing fluorescence resonance energy transfer in permeabilized myocytes, we specifically resolved RyR2-bound CaM from other potential binding targets and measured CaM-RyR2 binding affinity in situ (Kd=10-20 nmol/L). Using RyR2(ADA/+) knock-in mice, in which half of the CaM-RyR2 binding is suppressed, we estimated that >90% of Z-line CaM is RyR2-bound. Functional tests indicated a higher propensity for Ca2+ wave production and stress-induced ventricular arrhythmia in RyR2(ADA/+) mice. In a post-myocardial infarction rat heart failure model, we detected a decrease in the CaM-RyR2 binding affinity (Kd≈51 nmol/L; ≈3-fold increase) and unaltered RyR2 affinity for the FK506-binding protein FKBP12.6 (Kd~0.8 nmol/L).
conclusionsCaM binds to RyR2 with high affinity in cardiac myocytes. Physiologically, CaM is bound to >70% of RyR2 monomers and inhibits sarcoplasmic reticulum Ca2+ release. RyR2 is the major binding site for CaM along the Z-line in cardiomyocytes, and dissociating CaM from RyR2 can cause severe ventricular arrhythmia. In heart failure, RyR2 shows decreased CaM affinity, but unaltered FKBP 12.6 affinity.
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