ArticleThe Journal of biological chemistry2015
Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 40 citations in OpenAlex.
- Multiparametric Assessment of TNNI3 Variant Phenotypes in Human iPSC-Cardiomyocytes Correlates with Disease Severity in Patients.bioRxiv : the preprint server for biology · 2025Article
- Troponin I - a comprehensive review of its function, structure, evolution, and role in muscle diseases.Animal cells and systems · 2025Review
- Focus on cardiac troponin complex: From gene expression to cardiomyopathy.Genes & diseases · 2024Review
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.Journal of chemical information and modeling · 2023Article
- Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.bioRxiv : the preprint server for biology · 2023Article
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy.Scientific reports · 2022Article
- Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.Journal of chemical information and modeling · 2022Article
- Umbrella Sampling Simulations Measure Switch Peptide Binding and Hydrophobic Patch Opening Free Energies in Cardiac Troponin.Journal of chemical information and modeling · 2022Article
- Review
- Suppression of lusitropy as a disease mechanism in cardiomyopathies.Frontiers in cardiovascular medicine · 2022Review
- Cardiomyocyte Dysfunction in Inherited Cardiomyopathies.International journal of molecular sciences · 2021Review
- Computational Methods Elucidate Consequences of Mutations and Post-translational Modifications on Troponin I Effective Concentration to Troponin C.The journal of physical chemistry. B · 2021Article
- 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
- Cardiomyopathic troponin mutations predominantly occur at its interface with actin and tropomyosin.The Journal of general physiology · 2021Article
- Troponin structure and function: a view of recent progress.Journal of muscle research and cell motility · 2020Review
- New insights provided by myofibril mechanics in inherited cardiomyopathies.Conditioning medicine · 2019Article
- Multiscale Models of Cardiac Muscle Biophysics and Tissue Remodeling in Hypertrophic Cardiomyopathies.Current opinion in biomedical engineering · 2019Article
- Evaluation of cardiac hypertrophy in the setting of sudden cardiac death.Forensic sciences research · 2019Review
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Two hypertrophic cardiomyopathy-associated cardiac troponin I (cTnI) mutations, R146G and R21C, are located in different regions of cTnI, the inhibitory peptide and the cardiac-specific N terminus. We recently reported that these regions may interact when Ser-23/Ser-24 are phosphorylated, weakening the interaction of cTnI with cardiac TnC. Little is known about how these mutations influence the affinity of cardiac TnC for cTnI (KC-I) or contractile kinetics during β-adrenergic stimulation. Here, we tested how cTnI(R146G) or cTnI(R21C) influences contractile activation and relaxation and their response to protein kinase A (PKA). Both mutations significantly increased Ca(2+) binding affinity to cTn (KCa) and KC-I. PKA phosphorylation resulted in a similar reduction of KCa for all complexes, but KC-I was reduced only with cTnI(WT). cTnI(WT), cTnI(R146G), and cTnI(R21C) were complexed into cardiac troponin and exchanged into rat ventricular myofibrils, and contraction/relaxation kinetics were measured ± PKA phosphorylation. Maximal tension (Tmax) was maintained for cTnI(R146G)- and cTnI(R21C)-exchanged myofibrils, and Ca(2+) sensitivity of tension (pCa50) was increased. PKA phosphorylation decreased pCa50 for cTnI(WT)-exchanged myofibrils but not for either mutation. PKA phosphorylation accelerated the early slow phase relaxation for cTnI(WT) myofibrils, especially at Ca(2+) levels that the heart operates in vivo. Importantly, this effect was blunted for cTnI(R146G)- and cTnI(R21C)-exchanged myofibrils. Molecular dynamics simulations suggest both mutations inhibit formation of intra-subunit contacts between the N terminus and the inhibitory peptide of cTnI that is normally seen with WT-cTn upon PKA phosphorylation. Together, our results suggest that cTnI(R146G) and cTnI(R21C) blunt PKA modulation of activation and relaxation kinetics by prohibiting cardiac-specific N-terminal interaction with the cTnI inhibitory peptide.
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