| Project/Area Number |
12144210
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University, Graduate School of Engineering (2003-2004)
Okazaki National Research Institutes (2000-2002) |
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Principal Investigator |
MORI Eyasuo Kyoto University, Graduate, School of Engineering, Professor, 工学研究科, 教授 (80212265)
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| Co-Investigator(Kenkyū-buntansha) |
TAKESHIMA Hiroshi Tohoku University, Graduate School of Medicine, Professor, 薬学研究科, 教授 (70212024)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥34,400,000 (Direct Cost: ¥34,400,000)
Fiscal Year 2004: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2002: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 2001: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | gene / physiology / biotechnologv / pharmaco logy / cell, tissue / ion channel / 生体分子 / ノックアウトマウス / 上皮細胞 / Ca^<2+>シグナリング / Ca^<2+>チャネル / 小胞体 |
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| Research Abstract |
We have studied molecular identity of plasma membrane Ca^<2+>-permeable channels and endoplasmic reticulum (ER) Ca^<2+> release channels, and their functional properties, cellular localization, and coupling in epithelial cells, to establish molecular physiological basis underlying vectorization of Ca^<2+> signals in epithelial transport.
Abundant expression of receptor-activated TRPC channels was revealed in various epithelial cells. TRPC3, C5, C6, C7 were activated upon stimulation of G-protein-coupled receptors independently of depletion of Ca^<2+> stores/ Ca^<2+> release. TRPC5 was associated with eNOS in the plasma membrane invagination caveola in endothelial cells, and was activated by NO to mediate Ca^<2+> influx that controls a positive feedback loop for receptor-induced NO production cascade. The NAD-activated TRPM2 Ca^<2+> channel was also demonstrated to be linked to cell death under oxidative stress by reactive oxygen/nitrogen species or by TNF.
To understand molecular mechani
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sms that determine spatio-temporal patterns of Ca^<2+> signaling, we used chicken DT40 B lymphocytes to create a cell line deficient of TRPC1. The cells showed reduction in store-operated Ca^<2+> (SOC) entry, IP3 ; receptor-mediated Ca^<2+> release, and Ca^<2+> oscillation upon B cell receptor stimulation, suggesting that TRPC1 is critical for patterning Ca^<2+> signals. Furthermore, we demonstrated a positive feedback loop for Ca^<2+>/ IP_3 signaling : translocation and subsequent activation of phospholipase C (PLC)γ elicited by TRPC3-mediating Ca^<2+> entry.
For functional coupling between plasmamembrane and ER membrane in Ca^<2+> signaling, the junction structure formed by the two kinds of membrane is essential. To understand molecular architecture of the junction structure, we characterized molecules essential for the structure. Three Junctophilin members have been identified which contribute to formation of the junction structure in excitable cells. A junctional protein Mitsugumin29 plays an important role in ER Ca^<2+> release and SOC. Sarcalmenin in the lumen of sarcoplasmic reticulum (SR) contributes to Ca^<2+> storing capacity of SR. Less
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