title: Signal Transduction Mechanism for Serotonin 5-HT2B Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes.
abstract: The involvement of serotonin (5-hydroxytryptamine; 5-HT) and the 5-HT2 receptor subtypes in the induction of DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes to elucidate the intracellular signal transduction mechanisms. Hepatocyte parenchymal cells maintained in a serum-free, defined medium, synthesized DNA and proliferated in the presence of 5-HT or a selective 5-HT2B receptor agonist, BW723C86, but not in the presence of 5-HT2A, or 5-HT2C receptor agonists (TCB-2 and CP809101, respectively), in a time- and dose-dependent manner. A selective 5-HT2B receptor antagonist, LY272015 (10(-7) M), and a specific phospholipase C (PLC) inhibitor, U-73122 (10(-6) M), as well as specific inhibitors of growth-related signal transducers-including AG1478, LY294002, PD98059, and rapamycin-completely inhibited 5-HT (10(-6) M)- or BW723C86 (10(-6) M)-induced hepatocyte DNA synthesis and proliferation. Both 5-HT and BW723C86 were shown to significantly stimulate the phosphorylation of epidermal growth factor (EGF)/transforming growth factor (TGF)-α receptor tyrosine kinase (p175 kDa) and extracellular signal-regulated kinase (ERK) 2 on Western blot analysis. These results suggest that the proliferative mechanism of activating 5-HT is mediated mainly through 5-HT2B receptor-stimulated Gq/PLC and EGF/TGF-α-receptor/phosphatidylinositol 3-kinase (PI3K)/ERK2/mammalian target of rapamycin (mTOR) signaling pathways in primary cultured hepatocytes.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University.
authors.forename: Kota
authors.initials: K
authors.lastname: Naito
authors.forename: Chizuru
authors.initials: C
authors.lastname: Tanaka
authors.forename: Manami
authors.initials: M
authors.lastname: Mitsuhashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Moteki
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kimura
authors.forename: Hideshi
authors.initials: H
authors.lastname: Natsume
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ogihara
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D044348:Receptors, Serotonin, 5-HT2 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; D007211:Indoles; D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D013876:Thiophenes; D012701:Serotonin; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases