Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158

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Signal Transduction Mechanism for Serotonin 5-HT2B Receptor-Mediated DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes
Kota NaitoChizuru TanakaManami MitsuhashiHajime MotekiMitsutoshi KimuraHideshi NatsumeMasahiko Ogihara
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ジャーナル フリー 早期公開

論文ID: b15-00735

この記事には本公開記事があります。
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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 EGF/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/PI3K/ERK2/mTOR signaling pathways in primary cultured hepatocytes.
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© 2016 The Pharmaceutical Society of Japan
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