ArticleCirculation research2010
Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks.
Article in Circulation research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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90 citing papers in PubMed, 153 citations in OpenAlex.
- Local calcium dynamics and signalling in cardiomyocytes.Nature reviews. Cardiology · 2026Review
- Crosstalk between Ryanodine Receptor 2 Dysfunction and FK506-Binding Proteins in Pulmonary Hypertension.Cardiovascular drugs and therapy · 2026Review
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Precision Editing of Cyclophilin A Generates Cyclosporine and Voclosporin Resistant Cellular Therapies.Blood immunology & cellular therapy · 2026Article
- Structural and Functional Regulation of RyR2 in Cardiac Calcium Handling and Arrhythmogenesis.Biomedicines · 2026Review
- Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.The Journal of general physiology · 2025Article
- Time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy.The Journal of general physiology · 2025Article
- Role of ryanodine receptor cooperativity in CaThe Journal of physiology · 2024Article
- Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.Journal of molecular and cellular cardiology · 2024Article
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.International journal of molecular sciences · 2023Article
- Dantrolene inhibition of ryanodine channels (RyR2) in artificial lipid bilayers depends on FKBP12.6.The Journal of general physiology · 2023Article
- Molecular Mechanism of a FRET Biosensor for the Cardiac Ryanodine Receptor Pathologically Leaky State.bioRxiv : the preprint server for biology · 2023Article
- FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Targeting ryanodine receptors to treat human diseases.The Journal of clinical investigation · 2023Review
- Probing spatiotemporal PKA activity at the ryanodine receptor and SERCA2a nanodomains in cardomyocytes.Cell communication and signaling : CCS · 2022Article
- Review
- Synergistic FRET assays for drug discovery targeting RyR2 channels.Journal of molecular and cellular cardiology · 2022Article
- Nanoscale organization of ryanodine receptor distribution and phosphorylation pattern determines the dynamics of calcium sparks.PLoS computational biology · 2022Article
- Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases.International journal of molecular sciences · 2022Review
30 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
rationaleFK506-binding proteins FKBP12.6 and FKBP12 are associated with cardiac ryanodine receptors (RyR2), and cAMP-dependent protein kinase A (PKA)-dependent phosphorylation of RyR2 was proposed to interrupt FKBP12.6-RyR2 association and activate RyR2. However, the function of FKBP12.6/12 and role of PKA phosphorylation in cardiac myocytes are controversial.
objectiveTo directly measure in situ binding of FKBP12.6/12 to RyR2 in ventricular myocytes, with simultaneous Ca sparks measurements as a RyR2 functional index. METHODS AND
resultsWe used permeabilized rat and mouse ventricular myocytes, and fluorescently-labeled FKBP12.6/12. Both FKBP12.6 and FKBP12 concentrate at Z-lines, consistent with RyR2 and Ca spark initiation sites. However, only FKBP12.6 inhibits resting RyR2 activity. Assessment of fluorescent FKBP binding in myocyte revealed a high FKBP12.6-RyR2 affinity (K(d)=0.7+/-0.1 nmol/L) and much lower FKBP12-RyR2 affinity (K(d)=206+/-70 nmol/L). Fluorescence recovery after photobleach confirmed this K(d) difference and showed that it is mediated by k(off). RyR2 phosphorylation by PKA did not alter binding kinetics or affinity of FKBP12.6/12 for RyR2. Using quantitative immunoblots, we determined endogenous [FKBP12] in intact myocytes is approximately 1 micromol/L (similar to [RyR]), whereas [FKBP12.6] is <or=150 nmol/L.
conclusionsOnly 10% to 20% of endogenous myocyte RyR2s have FKBP12.6 associated, but virtually all myocyte FKBP12.6 is RyR2-bound (because of very high affinity). FKBP12.6 but not FKBP12 inhibits basal RyR2 activity. PKA-dependent RyR2 phosphorylation has no significant effect on binding of either FKBP12 or 12.6 to RyR2 in myocytes.
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