Parathyroid hormone induces protein kinase C but not adenylate cyclase in adult cardiomyocytes and regulates cyclic AMP levels via protein kinase C-dependent phosphodiesterase activity.
Adult ventricular cardiomyocytes have been identified as target cells for parathyroid hormone (PTH) but little is known about its signal transduction in these cells. In the present study the influence of PTH on cyclic AMP accumulation and the activity of protein kinase C (PKC) in cardiomyocytes was evaluated. A mid-regional synthetic fragment of PTH, PTH-(28-48), which exerts a hypertrophic effect on cardiomyocytes, increased the activity of membrane-associated PKC in a dose-dependent manner (1-100 nM). Activated membranous PKC was dependent on Ca2+ and sensitive to an inhibitor of Ca(2+)-dependent isoforms of PKC. When adenylate cyclase was stimulated by the addition of isoprenaline, a beta-adrenoceptor agonist, PTH-(28-48) antagonized cyclic AMP accumulation. This antagonistic effect of PTH-(28-48) could be mimicked by activation of PKC with a phorbol ester and inhibited by isobutylmethylxanthine, a phosphodiesterase inhibitor. An N-terminal synthetic fragment, PTH-(1-34), which includes an adenylate cyclase-activating domain, did not stimulate the accumulation of cyclic AMP in cardiomyocytes. The results demonstrate that in adult cardiomyocytes PTH (1) is able to stimulate PKC, (2) is not able to cause accumulation of cyclic AMP and (3) functionally antagonizes the effect of beta-adrenoceptor stimulation to increase cellular cyclic AMP concentrations via PKC-dependent phosphodiesterase activity.
Schlüter
K D
KD
Physiologisches Institut, Universität Giessen, Germany.
Weber
M
M
Piper
H M
HM
D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D009281:Naphthalenes / Q000494:pharmacology; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D009281:Naphthalenes; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C061465:calphostin complex; D000242:Cyclic AMP; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate