Elucidation of physiological significance of direct Ca^<2+> channel-phospholipase coupling in cell fate control
| Project/Area Number |
16390076
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Kyoto University |
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Principal Investigator |
MORI Yasuo Kyoto University, Graduate School of Engineering, Professor, 工学研究科, 教授 (80212265)
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| Co-Investigator(Kenkyū-buntansha) |
HARA Yuji Kyoto University, Graduate School of Engineering, Research Associate, 助手 (60362456)
NISHIDA Motohiro Kyushu University, Graduate School of Pharmaceutical Sciences, Lecturer, 薬学研究院, 講師 (90342641)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2005: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2004: ¥10,800,000 (Direct Cost: ¥10,800,000)
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| Keywords | Cell fate / Calcium channel / Cellular signal / receptor / calcium signal |
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| Research Abstract |
TRP superfamily proteins form plasma membrane cation channels acting as ‘sensors' for diverse cellular stimuli. TRPM2 is a Ca^<2+> permeable channel activated by redox statue changes such as oxidative stress. Although it has been suggested that Ca^<2+> influx via TRPM2 mediate cell death, its physiological significance is still elusive. TRPM2 is expressed in immunocytes such as monocytes and lymphocytes. In monocytic cell line U937, it is known that hydrogen peroxide (H_2O_2) induces chemotactic cytokine interleukin-8 (IL-8) production via Erk/NF-κB pathway and that IL-8 is produced via intracellular Ca^<2+> increases. Here, we reveal that oxidative stress-sensitive TRPM2 Ca^<2+> channels are crucial for H_2O_2-induced IL-8 production in U937. We also report physiological significance of the TRPM2 in vivo with regard to the above biological response by utilizing TRPM2 knockout mice.
We also demonstrate a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. TRPC1, C4, C5, V1, V3, and V4 of TRPC and TRPV families, commonly classified as receptor-activated channels and thermosensor channels, show prominent responses to nitric oxide (NO) to elicit Ca^<2+> entry in HEK293 cells. TRPC5 cysteine mutants, examined for NO responsiveness and susceptibility to S-nitrosylation, have revealed Cys553 and Cys558 as modification sites essential for the NO sensitivity. The responsive TRPs harbor conserved cysteines on the same N-terminal side of the pore region. Strikingly, membrane sidedness of reactive disulfide-induced activation via Cys553 modification suggests cytoplasmic accessibility to Cys553. Thus, multidisciplinary approach based upon chemical biology and physiology identifies the structural motif for NO-sensitive activation gate in TRP channels, establishing ‘NO sensors' as a new functional category extending over different TRP subfamilies.
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Report
(3 results)
Research Products
(49 results)
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[Journal Article] Comprehensive analysis of the ascidian genome reveals novel insights into the molecular evolution of ion channel genes2005
Author(s)
Okamura Y, Murata Y, Nakajo K, Iwasaki I, Ohtsuka Y, Tanaka-Kunishima M, Takahashi N, Hara Y, Yoshida T, Nishida M, Okado H, Watari H, Meinertzhagen IA, Nishino A, Satoh N, Takahashi K, Satou Y, Okada Y, Mori Y
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Journal Title
Physiological Genomics 222
Pages: 269-282
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] The role of canonical transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005
Author(s)
Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
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Journal Title
J. Biol. Chem. 280
Pages: 35346-35351
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] The role of canoincal transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005
Author(s)
Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
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Journal Title
J.Biol.Chem. 280
Pages: 35346-35351
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] The role of canonical transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels.2005
Author(s)
Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
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Journal Title
J.Biol.Chem. 280
Pages: 35346-35351
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[Book] Ca channel pharmacology book2004
Author(s)
Mori Y, Itsukaichi Y, Nishida M, Oka H.
Total Pages
27
Publisher
Ca^<2+> channel mutations and associated diseases. In "Ca channel pharmacology book"
Description
「研究成果報告書概要(和文)」より
Related Report
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