Effect of protein kinase C activation on sarcoplasmic reticulum function and apparent myofibrillar Ca2+ sensitivity in intact and skinned muscles from normal and diseased human myocardium.
Protein kinase C regulates the activity of a diverse group of cellular proteins including membrane ion channel proteins. Although protein kinase C and its substrate protein have been identified in both membrane and cytosolic fractions in the heart, the physiological role of this kinase in the regulation of cardiac function remains unknown. We examined the physiological role of protein kinase C by stimulating its activity with 12-deoxyphorbol 13 isobutyrate 20 acetate (DPBA) in human trabeculae carneae. This resulted in decreased peak isometric twitch force and peak intracellular sarcoplasmic reticulum calcium release as detected with aequorin. Furthermore, in the presence of DPBA, steady-state force-[Ca2+] relations were shifted to higher intracellular calcium concentrations, and the Hill coefficient was reduced, indicating a decrease in responsiveness of the myofilaments to calcium and a change in cooperativity among thin filament proteins, respectively. Thus, DPBA affects not only intracellular calcium concentration, but myofilament calcium interactions as well. The effect of DPBA on Ca2+ activation probably reflects phosphorylation of thin-filament regulatory proteins by protein kinase C.
Gwathmey
J K
JK
Department of Medicine, Charles A. Dana Research Institute, Boston, Mass.
Hajjar
R J
RJ
D000328:Adult; D000331:Aequorin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004789:Enzyme Activation; D006331:Heart Diseases / Q000378:metabolism*; D006652:Histological Techniques; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D013746:Tetany
D010703:Phorbol Esters; C047907:12-deoxyphorbol-13-isobutyrate-20-acetate; D000331:Aequorin; D011493:Protein Kinase C; D002118:Calcium