Effect of troponin I Ser23/24 phosphorylation on Ca2+-sensitivity in human myocardium depends on the phosphorylation background
Open accessAbstract
Protein kinase A (PKA)-mediated phosphorylation of Ser23/24 of cardiac troponin I (cTnI) causes a reduction in Ca(2+)-sensitivity of force development. This study aimed to determine whether the PKA-induced modulation of the Ca(2+)-sensitivity is solely due to cTnI phosphorylation or depends on the phosphorylation status of other sarcomeric proteins. Endogenous troponin (cTn) complex in donor cardiomyocytes was partially exchanged (up to 66+/-1%) with recombinant unphosphorylated human cTn and in failing cells similar exchange was achieved using PKA-(bis)phosphorylated cTn complex. Cardiomyocytes immersed in exchange solution without complex added served as controls. Partial exchange of unphosphorylated cTn complex in donor tissue significantly increased Ca(2+)-sensitivity (pCa(50)) to 5.50+/-0.02 relative to the donor control value (pCa(50)=5.43+/-0.04). Exchange in failing tissue with PKA-phosphorylated cTn complex did not change Ca(2+)-sensitivity relative to the failing control (pCa(50)=5.60+/-0.02). Subsequent treatment of the cardiomyocytes with the catalytic subunit of PKA significantly decreased Ca(2+)-sensitivity in donor and failing tissue. Analysis of phosphorylated cTnI species revealed the same distribution of un-, mono- and bis-phosphorylated cTnI in donor control and in failing tissue exchanged with PKA-phosphorylated cTn complex. Phosphorylation of myosin-binding protein-C in failing tissue was significantly lower compared to donor tissue. These differences in Ca(2+)-sensitivity in donor and failing cells, despite similar distribution of cTnI species, could be abolished by subsequent PKA-treatment and indicate that other targets of PKA are involved the reduction of Ca(2+)-sensitivity. Our findings suggest that the sarcomeric phosphorylation background, which is altered in cardiac disease, influences the impact of cTnI Ser23/24 phosphorylation by PKA on Ca(2+)-sensitivity.
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At least one report acknowledged that use of inotropic agents affected phosphorylation levels in samples.
“At least one of these reports acknowledged that the use of inotropic agents affected the level of phosphorylation in the samples”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Kooij et al. 2010
Other studies have shown a much higher extent of human cTnI phosphorylation, with unphosphorylated group as low as ~2-10%.
“other studies which have shown a much higher extent of human cTnI phosphorylation (with un-phosphorylated group accounting for as low as ~2–10%)”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Kooij, et al., 2010
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Small and large animal models in cardiac contraction research: advantages and disadvantages
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- Authors
- Kooij, V., Saes, M., Jaquet, K., Zaremba, R., Foster, D. B., Murphy, A. M., dos Remedios, C., van der Velden, J., & Stienen, G. J. M.
- Affiliations
- Amsterdam Cardiovascular Sciences (NL)
- St. Josef-Hospital (DE)
- Johns Hopkins University (US)
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 48
- Issue
- 5
- Pages
- 954-963
- ISSN
- 0022-2828 (ISSN-L)
- PMC
- PMC2854313
- OpenAlex
- W2139645827
- Cited by
- 73
- References
- 48
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 5 · 2014: 10 · 2013: 10 · 2012: 3
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institutes of Health (R01 HL 63038)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- cardiac troponin I, protein kinase A, calcium sensitivity, cardiomyocytes, heart failure, myosin binding protein C, force development
- MeSH terms
- Myosin Binding Protein C, Analysis of Variance, Calcium, Carrier Proteins, Humans, Myocardium, Phosphorylation, Sarcomeres, Blotting, Western, Troponin I, Myocytes, Cardiac
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