Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser(315)

Ellen Dirkx*, Olivier Cazorla, Robert W. Schwenk, Ilka Lorenzen-Schmidt, Sakthivel Sadayappan, Johan Van Lint, Lucie Carrier, Guillaume J. J. M. van Eys, Jan F. C. Glatz, Joost J. F. P. Luiken

*Corresponding author for this work

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Abstract

Dirkx E, Cazorla O, Schwenk RW, Lorenzen-Schmidt I, Sadayappan S, Van Lint J, Carrier L, van Eys GJ, Glatz JF, Luiken JJ. Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser(315). Am J Physiol Heart Circ Physiol 303: H323-H331, 2012. First published May 25, 2012; doi:10.1152/ajpheart. 00749.2011.-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 phosphorylation 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 Ca2+ sensitivity (pCa(50)) and maximal Ca2+-activated tension of contraction (Tmax). In cMyBP-C KO skinned myocytes, PKD increased pCa(50) but did not alter T-max. This suggests that cMyBP-C is not involved in PKD-mediated sensitization of myofilaments to Ca2+ but is essential for PKD-induced increase in T-max. 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 Ca2+ sensitivity and by an increased Tmax through phosphorylation of cMyBP-C.
Original languageEnglish
Pages (from-to)H323-H331
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume303
Issue number3
DOIs
Publication statusPublished - Aug 2012

Keywords

  • cardiomyocyte contractility
  • calcium sensitivity
  • protein kinase A
  • phospho-cardiac myosin-binding protein C-serine-315

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