1998 Fiscal Year Final Research Report Summary
Structure and function of ryanodine receptors
| Project/Area Number |
09470022
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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 pharmacology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TAKESHIMA Hiroshi The University of Tokyo, Graduated School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (70212024)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Ca^<2+> release channel / ryanodine receptor / intracellular Ca^<2+> / caffeine / muscle contraction / 筋収縮 |
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| Research Abstract |
The structure-function relationship of ryanodine receptor subtypes (namely, RyR-l, 2 and 3) have been investigated by means of molecular biological and genetic methords, for example in vitro mutagenesis and generation of knockout mice. Our major findings in this research project are listed below.
1. Generation and characterization of mutant mice lacking RyR-2. Because function of RyR-2 was unknown in embryonic heart, we have generated mutant mice lacking RyR-2. The results in the mutant mice showed non-essential function of RyR-2 for contraction of embryonic cardiac muscle cells, however, the RyR-2-deficient mice exhibiting cardiac arrest die around embryonic day 10. Our results obtained indicate that RyR-2 is essential for the maintenance of intracellular Ca^<2+> stores by regulating luminal resting Ca^<2+> levels in embryonic cardiac muscle cells.
2. Intramolecular functional regions on the primary structure of the ryanodine receptor. We have mapped a region critical for skeletal muscle excitation-contraction coupling to the called D2 region on the RyR-1 molecule in our cDNA expression system using RyRs-deficient muscle. By combination of cDNA expression and single channel measurement, we have located the Ca^<2+> release channel-forming domain and a portion (designated as D3 region) responsible for Ca^<2+> binding for channel inactivation on the RyR-1 molecule.
3. Identification of novel proteins localized in skeletal muscle triad junction. We have identified mitsugumin29 (MG29) and MG23 as novel transmembrane proteins from skeletal muscle the triad junction by isolating specific monoclonal antibodies and cloning cDNAs. MG29 was shown to be a novel member of the synaptophysin family, suggesting that the presynaptic region and triad junction share evolutionally related components.
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[Publications] Nishi, M., Houtani, T., Sato, K., Doi, T., Noda, Y., Mamiya, T., Kuno, J., Takeshima, H., Nukada, T., Nabeshima, T., Yamashita, T., Noda, T.& Sugimoto, T.: "Unrestrained nociceptive response and disregulation of hearing ability in mice lacking nociceptin/orphaninFQ receptor." EMBOJ.16. 1858-1864 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Ikemoto, T., Komazaki, S., Takeshima, H., Nishi, M., Noda, T., Iino, M.& Endo, M.: "Functional and morphological features of myocytes from mutant mice lacking both ryanodine receptors type 1 and type 3." J.Physiol.501. 305-312 (1997)
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[Publications] Suda, N., Franzius, D., Fleig, A., Nishimura, S., Bodding, M., Hoth, M., Takeshima, H.& Penner, R.: "Ca^<2+>-induced Ca^<2+> release in chinese hamster ovary (CHO) cells co-expressing dihydropyridine and ryanodine receptors." J.Gen.Physiol.109. 619-631 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Bhat, M.B., Zhao, J., Hayek, S., Freeman, E.C., Takeshima, H.& Ma, J.: "Deletion of amino acids 1641-2437 from the foot region of skeletal muscle ryanodine receptor alters the conduction properties of the Ca release channel." Biophys.J.73. 1320-1328 (1997)
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[Publications] Bhat, M.B., Zhao, J., Zang, W., Balke, W., Takeshima, H., Wier, W.G.& Ma, J.: "Caffeine-induced Ca^<2+> release from chinese hamster ovary cells expressing muscle ryanodine receptor.Effects on full-lenght and carboxyl-terminal portion of Ca^<2+> release channel." J.Gen.Physiol.110. 749-762 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Ueda, H., Yamaguchi, T., Tokuyama, S., Inoue, M., Nishi, M.& Takeshima, H.: "Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene." Neurosci.Lett.237. 136-138 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Takeshima, H., Shimuta, M., Komazaki, S., Ohmi, K., Nishi, M., Iino, M., Miyata, A.& Kangawa, K.: "Mitsugumin29, a novel synaptophysin family member from the triad junction in skeletal muscle." Biochem.J.331. 317-322 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Takeshima, H., Komazaki, S., Hirose, K., Nishi, M., Noda, T.& Iino, M.: "Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2." EMBOJ.17. 3309-3316 (1998)
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[Publications] Manabe, T., Noda, Y., Mamiya, T., Katagiri, H., Houtani, T., Nishi, M., Noda, T., Takahashi, T., Sugimoto, T., Nabeshima, T.& Takeshima, H.: "Facilitation of long-term potentiation and memory in mice lacking nociceptin receptor." Nature. 394. 577-581 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Shimura, M., Komazaki, S., Nishi, M., Iino, M., Nakagawara, K & Takeshima, H.: "Structure and expression of mitsugumin29 gene." FEBS Lett.431. 263-267 (1998)
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[Publications] Komazaki, S., Ikemoto, T., Takeshima, H., Iino, M., Endo, M.& Nakamura, H.: "Morphological abnormalities of adrenal grand and hypertrophy of liver in mutant mice lacking ryanodine receptors." Cell Tissue Res.294. 467-473 (1998)
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