期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 554, 期 -, 页码 11-21出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2014.04.017
关键词
Myofilament function; Protein phosphorylation; Cardiomyocyte; Troponin I; Protein kinase C
资金
- National Institute of Health (NIH) [R01 HL063038, NIH R01 HL76038]
- Netherlands Organization for Scientific Research (NWO)
- European Society of Cardiology Research Grant
Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in heart failure. While studies in rodents demonstrated that PKC-mediated Ser42/44 phosphorylation decreases maximal force and ATPase activity, PKC incubation of human cardiomyocytes did not affect maximal force. We investigated whether Ser42/44 pseudo-phosphorylation affects force development and ATPase activity using troponin exchange in human myocardium. Additionally, we studied if pseudo-phosphorylated Ser42/44 modulates length-dependent activation of force, which is regulated by protein kinase A (PKA)-mediated cTnI-Ser23/24 phosphorylation. Isometric force was measured in membrane-permeabilized cardiomyocytes exchanged with human recombinant wild-type troponin or troponin mutated at Ser42/44 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 PKA incubation. ATPase activity was measured in troponin-exchanged cardiac muscle strips. Compared to wild-type, 42D/44D decreased Ca2+-sensitivity without affecting maximal force in failing and donor cardiomyocytes. In donor myocardium, 42D/44D did not affect maximal ATPase activity or tension cost. Interestingly, 42D/44D blunted the length-dependent increase in Ca2+-sensitivity induced upon PKA mediated phosphorylation. Since the drop in Ca2+-sensitivity at physiological ca(2+)-concentrations is relatively large phosphorylation of Ser42/44 may result in a decrease of force and associated ATP utilization in the human heart. (C) 2014 Elsevier Inc. All rights reserved.
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