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Protein kinase D increases maximal Ca 2+ -activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser 315

Abstract : Dirkx E, Cazorla O, Schwenk RW, Lorenzen-Schmidt I, Sa-dayappan S, Van Lint J, Carrier L, van Eys GJ, Glatz JF, Luiken JJ. Protein kinase D increases maximal Ca 2ϩ-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser 315 .Cardiac myosin-binding protein C (cMyBP-C) is involved in the regulation of cardiac myofilament contraction. Recent evidence showed that protein kinase D (PKD) is one of the kinases that phosphorylate cMyBP-C. However, the mechanism by which PKD-induced cMyBP-C phos-phorylation affects cardiac contractile responses is not known. Using immunoprecipitation, we showed that, in contracting cardiomyocytes, PKD binds to cMyBP-C and phosphorylates it at Ser 315. The effect of PKD-mediated phosphorylation of cMyBP-C on cardiac myofilament function was investigated in permeabilized ventricular myocytes, isolated from wild-type (WT) and from cMyBP-C knockout (KO) mice, incubated in the presence of full-length active PKD. In WT myocytes, PKD increased both myofilament Ca 2ϩ sensitivity (pCa50) and maximal Ca 2ϩ-activated tension of contraction (Tmax). In cMyBP-C KO skinned myocytes, PKD increased pCa50 but did not alter Tmax. This suggests that cMyBP-C is not involved in PKD-mediated sensitization of myofilaments to Ca 2ϩ but is essential for PKD-induced increase in Tmax. Furthermore, the phosphorylation of both PKD-Ser 916 and cMyBP-C-Ser 315 was contraction frequency-dependent, suggesting that PKD-mediated cMyBP-C phosphorylation is operational primarily during periods of increased contractile activity. Thus, during high contraction frequency, PKD facilitates contraction of cardiomyocytes by increasing Ca 2ϩ sensitivity and by an increased Tmax through phosphorylation of cMyBP-C. cardiomyocyte contractility; calcium sensitivity; protein kinase A; phospho-cardiac myosin-binding protein C-serine-315
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Soumis le : lundi 13 avril 2020 - 15:25:15
Dernière modification le : vendredi 17 avril 2020 - 01:36:56

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Ellen Dirkx, Olivier Cazorla, Robert Schwenk, Ilka Lorenzen-Schmidt, Sakthivel Sadayappan, et al.. Protein kinase D increases maximal Ca 2+ -activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser 315. AJP - Heart and Circulatory Physiology, American Physiological Society, 2012, 303 (3), pp.H323 - H331. ⟨10.1152/ajpheart.00749.2011⟩. ⟨hal-01824324⟩

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