title: Down-regulation and differential restoration of cAMP responses upon transient phorbol ester treatment of primary osteoblastic cells.
abstract: We studied cAMP responses induced by parathyroid hormone (PTH), prostaglandin E2 (PGE2) and forskolin in foetal rat calvariae-derived osteoblastic cells after 24 h treatment with a protein kinase C (PKC) activating phorbol ester. After this treatment, meant to down-regulate PKC activity, all tested cAMP responses were attenuated and were indeed accompanied by a decline in PKC activity. PTH receptor affinity was not altered and PTH receptor number was only slightly lowered after 24 h phorbol ester treatment. These results indicate that modulation of the cAMP responses by 24 h PMA treatment was mainly caused by a general impairment of adenylyl cyclase activity. Removal of the phorbol ester and subsequent culture for 2 days rendered the cells hyper-responsive to PTH: the PTH-induced cAMP response was 2 to 3 times higher than in control cells. Again no change in binding affinity of the PTH receptor was observed and receptor number was just 10% lower than in control cells. The PGE2- and forskolin-induced cAMP responses were not higher than normal. So, transient phorbol ester treatment leads to a differential, agonist-dependent restoration of the cAMP signalling system.
authors.affiliation: Laboratory of Cell Biology and Histology, University of Leiden, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Bos
authors.forename: J M
authors.initials: JM
authors.lastname: Van der Meer
authors.forename: J H
authors.initials: JH
authors.lastname: Feyen
authors.forename: M P
authors.initials: MP
authors.lastname: Herrmann-Erlee
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation; D007700:Kinetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012886:Skull; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D010281:Parathyroid Hormone; D010703:Phorbol Esters; D010726:Phosphodiesterase Inhibitors; D018016:Receptors, Parathyroid Hormone; D005576:Colforsin; C008876:phorbol-12,13-didecanoate; D000242:Cyclic AMP; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine