Prolonged phorbol ester treatment down-regulates protein kinase C isozymes and increases contraction rate in neonatal cardiac myocytes.
We have determined the effects of chronic exposure to the protein kinase C (PKC) activating drug 4-beta phorbol 12-myristate-13-acetate (PMA) on PKC isozymes and the rate of spontaneous contraction in neonatal rat cardiac myocytes in culture. Western blot analyses revealed that a two day exposure to 0.1-1 nM PMA increased the total amount of delta PKC, whereas, 100 nM PMA concentrations caused a complete down-regulation of the alpha PKC and an 80 kDa zeta PKC-like protein. In addition, 100 nM PMA treatment for 2 days did not result in complete down-regulation of the beta, delta, and epsilon PKC isozymes in Western blot and immunocytochemical studies. We also found a PKC-mediated enhancement of the rate of contraction in these cells following prolonged exposure to PMA (1-100nM). Our studies suggest that this enhancement of contraction rate may be mediated by the beta, delta, or epsilon PKC isozymes. A better understanding of the role(s) of PKC isozymes in the modulation of cardiac functions may reveal selective targets for therapies of cardiac disorders.
Johnson
J A
JA
Department of Molecular Pharmacology, Stanford University School of Medicine, CA 94305-5332, USA.
Adak
S
S
Mochly-Rosen
D
D
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D009200:Myocardial Contraction; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage*
D007527:Isoenzymes; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate