Protein kinase C α and ε phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium

Autor: Nicky M. Boontje, Viola Kooij, Kornelia Jaquet, Ger J.M. Stienen, Cris dos Remedios, Jolanda van der Velden, R. Zaremba
Přispěvatelé: Physiology, ICaR - Heartfailure and pulmonary arterial hypertension
Rok vydání: 2009
Předmět:
Zdroj: Basic Research in Cardiology
Basic Research in Cardiology, 105(2), 289-300. D. Steinkopff-Verlag
Kooij, V, Boontje, N, Zaremba, R, Jaquet, K, dos Remedios, C, Stienen, G J M & van der Velden, J 2010, ' Protein kinase C alpha and epsilon phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium ', Basic Research in Cardiology, vol. 105, no. 2, pp. 289-300 . https://doi.org/10.1007/s00395-009-0053-z
ISSN: 1435-1803
0300-8428
DOI: 10.1007/s00395-009-0053-z
Popis: Previous studies indicated that the increase in protein kinase C (PKC)-mediated myofilament protein phosphorylation observed in failing myocardium might be detrimental for contractile function. This study was designed to reveal and compare the effects of PKCalpha- and PKCepsilon-mediated phosphorylation on myofilament function in human myocardium. Isometric force was measured at different [Ca2+] in single permeabilized cardiomyocytes from failing human left ventricular tissue. Activated PKCalpha and PKCepsilon equally reduced Ca2+ sensitivity in failing cardiomyocytes (DeltapCa50 = 0.08 +/- 0.01). Both PKC isoforms increased phosphorylation of troponin I- (cTnI) and myosin binding protein C (cMyBP-C) in failing cardiomyocytes. Subsequent incubation of failing cardiomyocytes with the catalytic subunit of protein kinase A (PKA) resulted in a further reduction in Ca2+ sensitivity, indicating that the effects of both PKC isoforms were not caused by cross-phosphorylation of PKA sites. Both isozymes showed no effects on maximal force and only PKCalpha resulted in a modest significant reduction in passive force. Effects of PKCalpha were only minor in donor cardiomyocytes, presumably because of already saturated cTnI and cMyBP-C phosphorylation levels. Donor tissue could therefore be used as a tool to reveal the functional effects of troponin T (cTnT) phosphorylation by PKCalpha. Massive dephosphorylation of cTnT with alkaline phosphatase increased Ca2+ sensitivity. Subsequently, PKCalpha treatment of donor cardiomyocytes reduced Ca2+ sensitivity (DeltapCa50 = 0.08 +/- 0.02) and solely increased phosphorylation of cTnT, but did not affect maximal and passive force. PKCalpha- and PKCepsilon-mediated phosphorylation of cMyBP-C and cTnI as well as cTnT decrease myofilament Ca2+ sensitivity and may thereby reduce contractility and enhance relaxation of human myocardium.
Databáze: OpenAIRE
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