Length-dependent activation is modulated by cardiac troponin I bisphosphorylation at Ser23 and Ser24 but not by Thr143 phosphorylation
| Autor: | Ger J.M. Stienen, Paul J.M. Wijnker, Vasco Sequeira, D. Brian Foster, Yuejin Li, Jolanda van der Velden, Anne M. Murphy, Cristobal G. dos Remedios |
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| Přispěvatelé: | Physics of Living Systems, Physiology, ICaR - Heartfailure and pulmonary arterial hypertension |
| Rok vydání: | 2014 |
| Předmět: |
Male
Sarcomeres Myofilament medicine.medical_specialty SDG 16 - Peace Contraction (grammar) Physiology macromolecular substances Sarcomere chemistry.chemical_compound Phosphoserine Myofibrils Physiology (medical) Internal medicine Troponin I medicine Humans Protein phosphorylation Myocytes Cardiac Phosphorylation Protein Kinase C Chemistry SDG 16 - Peace Justice and Strong Institutions Middle Aged musculoskeletal system Cyclic AMP-Dependent Protein Kinases Myocardial Contraction Justice and Strong Institutions Endocrinology Phosphothreonine cardiovascular system Biophysics Calcium Female Cardiology and Cardiovascular Medicine Myofibril Muscle Mechanics and Ventricular Function |
| Zdroj: | American Journal of Physiology. Heart and Circulatory Physiology, 306(8), H1171-H1181. American Physiological Society Wijnker, P J M, Sequeira Oliveira, V, Foster, D B, Li, Y J, dos Remedios, C G, Murphy, A M, Stienen, G J M & van der Velden, J 2014, ' Length-dependent activation is modulated by cardiac troponin I bisphosphorylation at Ser23 and Ser24 but not by Thr143 phosphorylation ', American Journal of Physiology. Heart and Circulatory Physiology, vol. 306, no. 8, pp. H1171-H1181 . https://doi.org/10.1152/ajpheart.00580.2013 |
| ISSN: | 0363-6135 |
| Popis: | Frank-Starling's law reflects the ability of the heart to adjust the force of its contraction to changes in ventricular filling, a property based on length-dependent myofilament activation (LDA). The threonine at amino acid 143 of cardiac troponin I (cTnI) is prerequisite for the length-dependent increase in Ca2+sensitivity. Thr143 is a known target of protein kinase C (PKC) whose activity is increased in cardiac disease. Thr143 phosphorylation may modulate length-dependent myofilament activation in failing hearts. Therefore, we investigated if pseudo-phosphorylation at Thr143 modulates length dependence of force using troponin exchange experiments in human cardiomyocytes. In addition, we studied effects of protein kinase A (PKA)-mediated cTnI phosphorylation at Ser23/24, which has been reported to modulate LDA. Isometric force was measured at various Ca2+concentrations in membrane-permeabilized cardiomyocytes exchanged with recombinant wild-type (WT) troponin or troponin mutated at the PKC site Thr143 or Ser23/24 into aspartic acid (D) or alanine (A) to mimic phosphorylation and dephosphorylation, respectively. In troponin-exchanged donor cardiomyocytes experiments were repeated after incubation with exogenous PKA. Pseudo-phosphorylation of Thr143 increased myofilament Ca2+sensitivity compared with WT without affecting LDA in failing and donor cardiomyocytes. Subsequent PKA treatment enhanced the length-dependent shift in Ca2+sensitivity after WT and 143D exchange. Exchange with Ser23/24 variants demonstrated that pseudo-phosphorylation of both Ser23 and Ser24 is needed to enhance the length-dependent increase in Ca2+sensitivity. cTnI pseudo-phosphorylation did not alter length-dependent changes in maximal force. Thus phosphorylation at Thr143 enhances myofilament Ca2+sensitivity without affecting LDA, while Ser23/24 bisphosphorylation is needed to enhance the length-dependent increase in myofilament Ca2+sensitivity. |
| Databáze: | OpenAIRE |
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