ArticleBiophysical journal2008
A novel mutant cardiac troponin C disrupts molecular motions critical for calcium binding affinity and cardiomyocyte contractility.
Article in Biophysical journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed.
- MicroBundleCompute: Automated segmentation, tracking, and analysis of subdomain deformation in cardiac microbundles.PloS one · 2024Article
- Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation.International journal of molecular sciences · 2023Review
- Mouse Models of Cardiomyopathies Caused by Mutations in Troponin C.International journal of molecular sciences · 2023Review
- Umbrella Sampling Simulations of Cardiac Thin Filament Reveal Thermodynamic Consequences of Troponin I Inhibitory Peptide Mutations.Journal of chemical information and modeling · 2023Article
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- Lower troponin expression in the right ventricle of rats explains interventricular differences in E-C coupling.The Journal of general physiology · 2022Article
- Microengineered platforms for characterizing the contractile function of in vitro cardiac models.Microsystems & nanoengineering · 2022Review
- A micromachined force sensing apparatus and method for human engineered cardiac tissue and induced pluripotent stem cell characterization.Sensors and actuators. A, Physical · 2021Article
- Cardiomyocyte Dysfunction in Inherited Cardiomyopathies.International journal of molecular sciences · 2021Review
- Calcium and Heart Failure: How Did We Get Here and Where Are We Going?International journal of molecular sciences · 2021Review
- Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.Journal of chemical information and modeling · 2021Article
- Structural Changes beyond the EF-Hand Contribute to Apparent Calcium Binding Affinities: Insights from Parvalbumins.The journal of physical chemistry. B · 2021Article
- A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C.Journal of muscle research and cell motility · 2021Article
- Increased myocyte calcium sensitivity in end-stage pediatric dilated cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2019Article
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
- Desensitizing mouse cardiac troponin C to calcium converts slow muscle towards a fast muscle phenotype.The Journal of physiology · 2018Article
- Molecular Dynamics and Umbrella Sampling Simulations Elucidate Differences in Troponin C Isoform and Mutant Hydrophobic Patch Exposure.The journal of physical chemistry. B · 2018Article
- Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype.Frontiers in physiology · 2017Review
- Molecular Effects of cTnC DCM Mutations on Calcium Sensitivity and Myofilament Activation-An Integrated Multiscale Modeling Study.The journal of physical chemistry. B · 2016Article
- Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice.Bioscience reports · 2016Article
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Authors and funding
13 authors.
Funding
Abstract
Troponin C (TnC) belongs to the superfamily of EF-hand (helix-loop-helix) Ca(2+)-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca(2+)-binding Site II of TnC, TnC((E59D,D75Y)). Expression of recombinant TnC((E59D,D75Y)) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC(D75Y) was able to recapitulate the TnC((E59D,D75Y)) phenotype, whereas TnC(E59D) was functionally benign. Force-pCa relationships in TnC((E59D,D75Y)) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC((E59D,D75Y)) labeled with 2-[(4'-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca(2+) sensitivity and Ca(2+) binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca(2+)-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca(2+)-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype.
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Registered trials
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