1998 Fiscal Year Final Research Report Summary
Molecular Cloning and Signal Transduction of Leukotriene Receptors
| Project/Area Number |
09670147
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
IZUMI Takashi The University of Tokyo, Graduate School of Medicine, Associate professor, 大学院・医学系研究科, 助教授 (70232361)
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| Co-Investigator(Kenkyū-buntansha) |
KUME Kazuhiko The University of Tokyo, Graduate School of Medicine, Associate professor, 大学院・医学系研究科, 助手 (30251218)
SHIMIZU Takao The University of Tokyo, Graduate School of Medicine, Associate professor, 大学院・医学系研究科, 教授 (80127092)
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| Project Period (FY) |
1997 – 1998
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| Keywords | LTB4 Receptor / LTD4 Receptor / Molecular cloning / Signal Transdiction |
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| Research Abstract |
Leukotrienes are major lipid mediators involved in inflammatory and allergic disorders. Despite their potent biological activities, little is known about the receptors and intracellular signaling pathways.
1.We cloned a cDNA for a LTB_4 receptor (BLT) from HL-60 cells differentiated with retinoic acid using a subtraction strategy. The open reading frame (ORF) of the cDNA encodes a protein of 352 amino acids and is predicted to contain seven membrane-spanning domains. In CHO cells stably expressing BLT, LTB_4 elicited many signal transductions such as increase in intracellular calcium, InsP_3 accumulation, and inhibition of adenylyl cyclase. The CHO cells revealed a marked chemotactic response toward nM order of LTB_4. Calcium increase and InsP_3 accumulation induced by LTB_4 were partially sensitive to pertussis toxin (PTX), while chemotaxis and inhibition of adenylate cyclase were completely sensitive to PTX, indicating that BLT transduces LTB_4 signals through both PTX-sensitive and -insensitive G proteins.
2.We analyzed the signal transduction mechanisms through LTD_4 receptors using human monocytic leukemia THP-1 cells. When these cells were stimulated with LTD_4, intracellular calcium concentration was increased and mitogen-activated protein kinase (MAP kinase) was activated. A chemotactic response of THP-1 cells toward LTD_4 was also observed. We found that LTD_4 has at least two distinct signaling pathways in THP-1 cells, a PTX-insensitive mitogen-activated protein kinase activation through protein kinase Calpha and Raf-1 and a PTX-sensitive chemotactic response. This cellular signaling can explain in part the versatile activities of LTD_4 in macrophages under inflammatory and allergic conditions.
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[Publications] Ishii, S., Nakamura, M., Waga, I., Kume., K., Izumi, T., et al.: "Cloning and characterization of a platelet-activating factor receptor gene." Adv.Exp.Med.Biol.407. 347-355 (1997)
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[Publications] Izumi, T., Yokomizo, T., Igarashi, T., Shimizu, T.: "Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Related Diseases, 4" Molecular cloning and characterization of leukotriene B4 receptor. (in press), (1999)
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