ArticlePloS one2012
FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 66 citations in OpenAlex.
- Engineering human Tregs to resist tacrolimus via FKBP12 gene editing.Frontiers in immunology · 2026Article
- 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
- 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
- Dantrolene inhibition of ryanodine channels (RyR2) in artificial lipid bilayers depends on FKBP12.6.The Journal of general physiology · 2023Article
- Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor.Aging cell · 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
- Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.International journal of molecular sciences · 2023Article
- Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.Science advances · 2023Article
- Structural Insight Into Ryanodine Receptor Channelopathies.Frontiers in pharmacology · 2022Review
- Mutation in RyR2-FKBP Binding site alters CaCell calcium · 2022Article
- Mounting evidence of FKBP12 implication in neurodegeneration.Neural regeneration research · 2020Review
- Article
- Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Blocking the FKBP12 induced dendrimeric burst in aberrant aggregation of α-synuclein by using the ElteN378 synthetic inhibitor.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse.Journal of cell science · 2019Article
- Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12.American journal of physiology. Heart and circulatory physiology · 2019Article
- Unbalance Between Sarcoplasmic Reticulum CaFrontiers in physiology · 2019Review
- Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour.Scientific reports · 2018Article
- Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform.British journal of pharmacology · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Changes in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca(2+)-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca(2+)-induced Ca(2+)-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca(2+), whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca(2+)-wave frequency and decreased the SR Ca(2+)-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12.We provide a biophysical analysis of the mechanisms by which FK-binding proteins can regulate RyR2 single-channel gating. Our data indicate that FKBP12, in addition to FKBP12.6, may be important in regulating RyR2 function in the heart. In heart failure, it is possible that an alteration in the dual regulation of RyR2 by FKBP12 and FKBP12.6 may occur. This could contribute towards a higher RyR2 open probability, 'leaky' RyR2 channels and Ca(2+)-dependent arrhythmias.
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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.