Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser315.
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Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser315. / Dirkx, Ellen; Cazorla, Olivier; Schwenk, Robert W; Lorenzen-Schmidt, Ilka; Sadayappan, Sakthivel; Johan, Van Lint; Carrier, Lucie; Eys, van; Guillaume, J J M; Glatz, Jan F C; Luiken, Joost J F P.
in: AM J PHYSIOL-HEART C, Jahrgang 303, Nr. 3, 3, 2012, S. 323-331.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser315.
AU - Dirkx, Ellen
AU - Cazorla, Olivier
AU - Schwenk, Robert W
AU - Lorenzen-Schmidt, Ilka
AU - Sadayappan, Sakthivel
AU - Johan, Van Lint
AU - Carrier, Lucie
AU - Eys, van
AU - Guillaume, J J M
AU - Glatz, Jan F C
AU - Luiken, Joost J F P
PY - 2012
Y1 - 2012
N2 - 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 Ca(2+) sensitivity (pCa(50)) and maximal Ca(2+)-activated tension of contraction (T(max)). 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 Ca(2+) 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 Ca(2+) sensitivity and by an increased T(max) through phosphorylation of cMyBP-C.
AB - 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 Ca(2+) sensitivity (pCa(50)) and maximal Ca(2+)-activated tension of contraction (T(max)). 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 Ca(2+) 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 Ca(2+) sensitivity and by an increased T(max) through phosphorylation of cMyBP-C.
KW - Animals
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Rats
KW - Electric Stimulation
KW - Phosphorylation
KW - Immunoprecipitation
KW - Protein Binding
KW - Rats, Inbred Lew
KW - Adrenergic beta-Antagonists/pharmacology
KW - Carrier Proteins/genetics/metabolism
KW - Excitation Contraction Coupling/drug effects
KW - Myocardial Contraction/drug effects
KW - Myocytes, Cardiac/drug effects/enzymology
KW - Myofibrils/enzymology
KW - Protein Kinase C/metabolism
KW - Serine
KW - Animals
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Rats
KW - Electric Stimulation
KW - Phosphorylation
KW - Immunoprecipitation
KW - Protein Binding
KW - Rats, Inbred Lew
KW - Adrenergic beta-Antagonists/pharmacology
KW - Carrier Proteins/genetics/metabolism
KW - Excitation Contraction Coupling/drug effects
KW - Myocardial Contraction/drug effects
KW - Myocytes, Cardiac/drug effects/enzymology
KW - Myofibrils/enzymology
KW - Protein Kinase C/metabolism
KW - Serine
M3 - SCORING: Journal article
VL - 303
SP - 323
EP - 331
JO - AM J PHYSIOL-HEART C
JF - AM J PHYSIOL-HEART C
SN - 0363-6135
IS - 3
M1 - 3
ER -
