ArticleThe journal of physical chemistry. B2016
Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation.
Article in The journal of physical chemistry. B, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- 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
- Dysfunctional sarcomeric relaxation in the heart.Current opinion in physiology · 2022Article
- Suppression of lusitropy as a disease mechanism in cardiomyopathies.Frontiers in cardiovascular medicine · 2022Review
- 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
- 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
- Computational Studies of Cardiac and Skeletal Troponin.Frontiers in molecular biosciences · 2019Review
- Molecular Dynamics and Umbrella Sampling Simulations Elucidate Differences in Troponin C Isoform and Mutant Hydrophobic Patch Exposure.The journal of physical chemistry. B · 2018Article
- Mechanistic complexity of contractile dysfunction in hypertrophic cardiomyopathy.The Journal of general physiology · 2018Article
- Contribution of Post-translational Phosphorylation to Sarcomere-Linked Cardiomyopathy Phenotypes.Frontiers in physiology · 2016Article
- The Importance of Intrinsically Disordered Segments of Cardiac Troponin in Modulating Function by Phosphorylation and Disease-Causing Mutations.Frontiers in physiology · 2016Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
cTnI(P82S) (cTnI(P83S) in rodents) resides at the I-T arm of cardiac troponin I (cTnI) and was initially identified as a disease-causing mutation of hypertrophic cardiomyopathy (HCM). However, later studies suggested this may not be true. We recently reported that introduction of an HCM-associated mutation in either inhibitory-peptide (cTnI(R146G)) or cardiac-specific N-terminus (cTnI(R21C)) of cTnI blunts the PKA-mediated modulation on myofibril activation/relaxation kinetics by prohibiting formation of intrasubunit contacts between these regions. Here, we tested whether this also occurs for cTnI(P83S). cTnI(P83S) increased both Ca(2+) binding affinity to cTn (KCa) and affinity of cTnC for cTnI (KC-I), and eliminated the reduction of KCa and KC-I observed for phosphorylated-cTnI(WT). In isolated myofibrils, cTnI(P83S) maintained maximal tension (TMAX) and Ca(2+) sensitivity of tension (pCa50). For cTnI(WT) myofibrils, PKA-mediated phosphorylation decreased pCa50 and sped up the slow-phase relaxation (especially for those Ca(2+) conditions that heart performs in vivo). Those effects were blunted for cTnI(P83S) myofibrils. Molecular-dynamics simulations suggested cTnI(P83S) moderately inhibited an intrasubunit interaction formation between inhibitory-peptide and N-terminus, but this "blunting" effect was weaker than that with cTnI(R146G) or cTnI(R21C). In summary, cTnI(P83S) has similar effects as other HCM-associated cTnI mutations on troponin and myofibril function even though it is in the I-T arm of cTnI.
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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.