title: Signal transduction mechanism for potentiation by α1- and β2-adrenoceptor agonists of L-ascorbic acid-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.
abstract: We investigated the effects of α- and β-adrenoceptor agonists on L-ascorbic acid-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. The results showed that phenylephrine (10(-6) M) and metaproterenol (10(-6) M) alone did not induce hepatocyte DNA synthesis and proliferation. However, when combined with L-ascorbic acid (10(-6) M), these adrenoceptor agonists potentiated the hepatocyte DNA synthesis and proliferation induced by L-ascorbic acid. Then intracellular signal transduction mechanisms for the effects of phenylephrine and metaproterenol on L-ascorbic acid-induced hepatocyte mitogenesis were examined. Western blot analysis showed that phenylephrine and metaproterenol did not potentiate L-ascorbic acid-induced insulin-like growth factor I receptor tyrosine kinase phosphorylation. In contrast, they both significantly potentiated L-ascorbic acid-induced extracellular-signal regulated kinase-2 (ERK2) phosphorylation within 5 min. Moreover, cell-permeable second messenger analogs phorbol ester (10(-7) M) and 8-bromo cAMP (10(-7) M) mimicked the effects of phenylephrine and metaproterenol on L-ascorbic acid-induced ERK2 phosphorylation. The effects of these adrenoceptor agents were specifically antagonized by GF109203X and H-89, respectively. These results indicate that activation of ERK2 via protein kinas C and protein kinase A represents a mechanism for potentiation of L-ascorbic acid-induced hepatocyte DNA synthesis and proliferation in primary cultures of adult rat hepatocytes.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Moteki
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kimura
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Sunaga
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tsuda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ogihara
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009921:Metaproterenol / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018340:Receptors, Adrenergic, alpha-1; D018343:Receptors, Adrenergic, beta-2; D010656:Phenylephrine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009921:Metaproterenol; D004247:DNA; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate; D001205:Ascorbic Acid