Effect of Selective Serotonin (5-HT)[2B] Receptor Agonist BW723C86 on Epidermal Growth Factor/Transforming Growth Factor-α Receptor Tyrosine Kinase and Ribosomal p70 S6 Kinase Activities in Primary Cultures of Adult Rat Hepatocytes

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  • Naito Kota
    Departments of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
  • Kurihara Kazuki
    Departments of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
  • Moteki Hajime
    Departments of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
  • Kimura Mitsutoshi
    Departments of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University
  • Natsume Hideshi
    Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Josai University
  • Ogihara Masahiko
    Departments of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University

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  • Effect of Selective Serotonin (5-HT)<sub>2B</sub> Receptor Agonist BW723C86 on Epidermal Growth Factor/Transforming Growth Factor-α Receptor Tyrosine Kinase and Ribosomal p70 S6 Kinase Activities in Primary Cultures of Adult Rat Hepatocytes

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<p>Serotonin (5-hydroxytryptamine; 5-HT) can induce hepatocyte DNA synthesis and proliferation by autocrine secretion of transforming growth factor (TGF)-α through 5-HT2B receptor/phospholipase C (PLC)/Ca2+ and a signaling pathway involving epidermal growth factor (EGF)/TGF-α receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase 2 (ERK2)/mammalian target of rapamycin (mTOR). In the present study, we investigated whether 5-HT or a selective 5-HT2B receptor agonist BW723C86, would stimulate phosphorylation of TGF-α RTK and ribosomal p70 S6 kinase (p70S6K) in primary cultures of adult rat hepatocytes. Western blotting analysis was used to detect 5-HT- or BW723C86 (10−6 M)-induced phosphorylation of EGF/TGF-α RTK and p70S6K. Our results showed that 5-HT- or BW723C86 (10−6 M)-induced phosphorylation of EGF/TGF-α RTK peaked at between 5 and 10 min. On the other hand, 5-HT- or BW723C86 (10−6 M)-induced phosphorylation of p70S6K peaked at about 30 min. Furthermore, a selective 5-HT2B receptor antagonist LY272015, a specific PLC inhibitor U-73122, a membrane-permeable Ca2+ chelator BAPTA/AM, an L-type Ca2+ channel blocker verapamil, somatostatin, and a specific p70S6K inhibitor LY2584702 completely abolished the phosphorylation of p70S6K induced by both 5-HT and BW723C86. These results indicate that phosphorylation of p70S6K is dependent on the 5-HT2B-receptor-mediated autocrine secretion of TGF-α. In addition, these results demonstrate that the hepatocyte proliferating action of 5-HT and BW723C86 are mediated by phosphorylation of p70S6K, a downstream element of the EGF/TGF-α RTK signaling pathway.</p>

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