scholarly journals β-Adrenergic augmentation of cardiac contractility is dependent on PKA-mediated phosphorylation of myosin-binding protein C and troponin I

2016 ◽  
Vol 594 (17) ◽  
pp. 4707-4708 ◽  
Author(s):  
Neal Ingraham Callaghan
Keyword(s):  
Protein C ◽  
Troponin I ◽  
Binding Protein ◽  
Cardiac Contractility ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals The Interplay between S-glutathionylation and Phosphorylation of Cardiac Troponin I and Myosin Binding Protein C in End-Stage Human Failing Hearts

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1134
Author(s):  
Heidi Budde ◽  
Roua Hassoun ◽  
Melina Tangos ◽  
Saltanat Zhazykbayeva ◽  
Melissa Herwig ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein C ◽  
Troponin I ◽  
Reduced Glutathione ◽  
Binding Protein ◽  
Enzyme Treatment ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
End Stage

Oxidative stress is defined as an imbalance between the antioxidant defense system and the production of reactive oxygen species (ROS). At low levels, ROS are involved in the regulation of redox signaling for cell protection. However, upon chronical increase in oxidative stress, cell damage occurs, due to protein, DNA and lipid oxidation. Here, we investigated the oxidative modifications of myofilament proteins, and their role in modulating cardiomyocyte function in end-stage human failing hearts. We found altered maximum Ca2+-activated tension and Ca2+ sensitivity of force production of skinned single cardiomyocytes in end-stage human failing hearts compared to non-failing hearts, which was corrected upon treatment with reduced glutathione enzyme. This was accompanied by the increased oxidation of troponin I and myosin binding protein C, and decreased levels of protein kinases A (PKA)- and C (PKC)-mediated phosphorylation of both proteins. The Ca2+ sensitivity and maximal tension correlated strongly with the myofilament oxidation levels, hypo-phosphorylation, and oxidative stress parameters that were measured in all the samples. Furthermore, we detected elevated titin-based myocardial stiffness in HF myocytes, which was reversed by PKA and reduced glutathione enzyme treatment. Finally, many oxidative stress and inflammation parameters were significantly elevated in failing hearts compared to non-failing hearts, and corrected upon treatment with the anti-oxidant GSH enzyme. Here, we provide evidence that the altered mechanical properties of failing human cardiomyocytes are partially due to phosphorylation, S-glutathionylation, and the interplay between the two post-translational modifications, which contribute to the development of heart failure.

scholarly journals Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics

2004 ◽  
Vol 558 (3) ◽  
pp. 927-941 ◽  
Author(s):  
Carl W. Tong ◽  
Robert D. Gaffin ◽  
David C. Zawieja ◽  
Mariappan Muthuchamy
Keyword(s):  
Cardiac Muscle ◽  
Protein C ◽  
Troponin I ◽  
Binding Protein ◽  
Muscle Twitch ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

scholarly journals Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation

2015 ◽  
Vol 290 (49) ◽  
pp. 29241-29249 ◽  
Author(s):  
Mohit Kumar ◽  
Suresh Govindan ◽  
Mengjie Zhang ◽  
Ramzi J. Khairallah ◽  
Jody L. Martin ◽  
...  
Keyword(s):  
Protein C ◽  
Troponin I ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Length Dependent Activation

scholarly journals Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin

2019 ◽  
pp. 201821660 ◽  
Author(s):  
James W. McNamara ◽  
Rohit R. Singh ◽  
Sakthivel Sadayappan
Keyword(s):  
Protein C ◽  
Contractile Function ◽  
Binding Protein ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Detectable Effect ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) accelerates cardiac contractility. However, the mechanisms by which cMyBP-C phosphorylation increases contractile kinetics have not been fully elucidated. In this study, we tested the hypothesis that phosphorylation of cMyBP-C releases myosin heads from the inhibited super-relaxed state (SRX), thereby determining the fraction of myosin available for contraction. Mice with various alanine (A) or aspartic acid (D) substitutions of the three main phosphorylatable serines of cMyBP-C (serines 273, 282, and 302) were used to address the association between cMyBP-C phosphorylation and SRX. Single-nucleotide turnover in skinned ventricular preparations demonstrated that phosphomimetic cMyBP-C destabilized SRX, whereas phospho-ablated cMyBP-C had a stabilizing effect on SRX. Strikingly, phosphorylation at serine 282 site was found to play a critical role in regulating the SRX. Treatment of WT preparations with protein kinase A (PKA) reduced the SRX, whereas, in nonphosphorylatable cMyBP-C preparations, PKA had no detectable effect. Mice with stable SRX exhibited reduced force production. Phosphomimetic cMyBP-C with reduced SRX exhibited increased rates of tension redevelopment and reduced binding to myosin. We also used recombinant myosin subfragment-2 to disrupt the endogenous interaction between cMyBP-C and myosin and observed a significant reduction in the population of SRX myosin. This peptide also increased force generation and rate of tension redevelopment in skinned fibers. Taken together, this study demonstrates that the phosphorylation-dependent interaction between cMyBP-C and myosin is a determinant of the fraction of myosin available for contraction. Furthermore, the binding between cMyBP-C and myosin may be targeted to improve contractile function.

scholarly journals Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

2021 ◽  
Author(s):  
Thomas L. Lynch ◽  
Mohit Kumar ◽  
James W. McNamara ◽  
Diederik W.D. Kuster ◽  
Mayandi Sivaguru ◽  
...  
Keyword(s):  
Protein C ◽  
Binding Protein ◽  
Cardiac Contractility ◽  
Amino Terminus ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding
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