Protein kinase D increases maximal Ca2+ activated tension of cardiomyocyte contraction by selective phosphorylation of cMyBP‐C‐Ser315

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Cardiac myosin binding protein-C (cMyBP-C) regulates cardiac myofilament contraction. Recent evidence showed that Protein kinase-D (PKD) is a kinase that phosphorylates cMyBP-C. However, the mechanism by which PKD-induced cMyBP-C phosphorylation mediates cardiac contractile responses is not known yet. Using immunoprecipitation, PKD was shown to bind to cMyBP-C and to phosphorylate it at Ser315 in contracting cardiomyocytes. 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 cMyBP-C knock-out (KO) mice. In WT myocytes, PKD increased both myofilament Ca2+ sensitivity (pCa50) and maximal Ca2+-activated tension of contraction (Tmax). The PKD-induced increase of Tmax and sub-maximal active tension was not observed in cMyBP-C KO myocytes, which proofs that cMyBP-C is involved in the PKD-mediated increase of submaximal activation and Tmax. Furthermore, phosphorylation of both PKD-Ser916 and cMyBP-C-Ser315 is contraction frequency-dependent, indicating that PKD-mediated cMyBP-C phosphorylation is operational especially during periods of increased contractile activity. We propose that during increased contraction, PKD is a key factor to match energy metabolism and cardiac mechanics. Grant Funding Source: NWO (Dutch foundation for scientific research)