Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes

• Verfasst von: Cuello, Friederike [VerfasserIn]
• Verfasst von: Bardswell, Sonya C. [VerfasserIn]
• Verfasst von: Haworth, Robert S. [VerfasserIn]
• Verfasst von: Yin, Xiaoke [VerfasserIn]
• Verfasst von: Lutz, Susanne [VerfasserIn]
• Verfasst von: Wieland, Thomas [VerfasserIn]
• Verfasst von: Mayr, Manuel [VerfasserIn]
• Verfasst von: Kentish, Jonathan C. [VerfasserIn]
• Verfasst von: Avkiran, Metin [VerfasserIn]
• Titel: Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes
• Verf.angabe: Friederike Cuello, Sonya C. Bardswell, Robert S. Haworth, Xiaoke Yin, Susanne Lutz, Thomas Wieland, Manuel Mayr, Jonathan C. Kentish, Metin Avkiran
• E-Jahr: 2007
• Jahr: 22 February 2007
• Umfang: 10 S.
• Fussnoten: Gesehen am 24.03.2022 ; Im Text ist "2+" hochgestellt
• Titel Quelle: Enthalten in: Circulation research
• Ort Quelle: New York, NY : Assoc., 1953
• Jahr Quelle: 2007
• Band/Heft Quelle: 100(2007), 6, Seite 864-873
• ISSN Quelle: 1524-4571
• DOI: doi:10.1161/01.RES.0000260809.15393.fa
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: c family
• Sach-SW: calcium sensitivity
• Sach-SW: cardiac troponin I
• Sach-SW: contractile function
• Sach-SW: expression
• Sach-SW: heart-failure
• Sach-SW: member
• Sach-SW: molecular-cloning
• Sach-SW: myocardium
• Sach-SW: phosphorylation
• Sach-SW: pkd
• Sach-SW: protein kinase D
• Sach-SW: protein phosphorylation
• Sach-SW: vivo
• Sach-SW: z-discs
• K10plus-PPN: 1796563285

Abstract

Protein kinase D ( PKD) is a serine/threonine kinase with emerging myocardial functions; in skinned adult rat ventricular myocytes ( ARVMs), recombinant PKD catalytic domain phosphorylates cardiac troponin I at Ser22/Ser23 and reduces myofilament Ca2+ sensitivity. We used adenoviral gene transfer to determine the effects of full-length PKD on protein phosphorylation, sarcomere shortening and [ Ca2+](i) transients in intact ARVMs. In myocytes transduced to express wild-type PKD, the heterologously expressed enzyme was activated by endothelin 1 ( ET1) ( 5 nmol/L), as reflected by PKD phosphorylation at Ser744/Ser748 ( PKC phosphorylation sites) and Ser916 ( autophosphorylation site). The ET1-induced increase in cellular PKD activity was accompanied by increased cardiac troponin I phosphorylation at Ser22/Ser23; this measured approximately 60% of that induced by isoproterenol ( 10 nmol/L), which activates cAMP-dependent protein kinase ( PKA) but not PKD. Phosphorylation of other PKA targets, such as phospholamban at Ser16, phospholemman at Ser68 and cardiac myosin-binding protein C at Ser282, was unaltered. Furthermore, heterologous PKD expression had no effect on isoproterenol-induced phosphorylation of these proteins, or on isoproterenol-induced increases in sarcomere shortening and relaxation rate and [ Ca2+](i) transient amplitude. In contrast, heterologous PKD expression suppressed the positive inotropic effect of ET1 seen in control cells, without altering ET1-induced increases in relaxation rate and [ Ca2+](i) transient amplitude. Complementary experiments in "skinned" myocytes confirmed reduced myofilament Ca2+ sensitivity by ET1-induced activation of heterologously expressed PKD. We conclude that increased myocardial PKD activity induces cardiac troponin I phosphorylation at Ser22/Ser23 and reduces myofilament Ca2+ sensitivity, suggesting that altered PKD activity in disease may impact on contractile function.