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Studies on the molecular mechanisms underlying anxiety and convulsion with special reference to the roles for PRIP

Research Project

Project/Area Number 14370595
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionKyushu University

Principal Investigator

HIRATA Masato  Kyushu University, Faculty of Dental Science, Professor, 大学院・歯学研究院, 教授 (60136471)

Co-Investigator(Kenkyū-buntansha) MATSUDA Miho  Kyushu University, Faculty of Dental Science, Research Associate, 大学院・歯学研究院, 助手 (40291520)
KANEMATSU Takashi  Kyushu University, Faculty of Dental Science, Associate Professor, 大学院・歯学研究院, 助教授 (10264053)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2002: ¥9,900,000 (Direct Cost: ¥9,900,000)
KeywordsIns(1,4,5)P_3 / GABA_A receptor / GABARAP / knock-out mice / anti-anxiety drugs / hippocampus
Research Abstract

The protein PRIP was isolated from rat brain as an inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-δ1 but lacking PLC activity. In this study, we show that PRIP plays an important role in signaling by the type A receptor for γ-aminobutyric acid(GABA). Yeast two-hybrid screening identified GABARAP(GABA_A receptor-associated protein), which is proposed to contribute to the sorting, targeting, or clustering of GABA_A receptors, and PP1(protein phosphatase 1), as proteins that interact with PRIP. PRIP competitively inhibited the binding of the γ2 subunit of the GABA_A receptor to GABARAP in vitro. Electrophysiological analysis revealed that the modulation of GABA-induced Cl^-current by Zn^<2+> or diazepam, both of which act at GABA_A receptors containing y subunits, is impaired in hippocampal neurons of PRIP knockout mice(PRIP^<-/->mice). Behavioral analysis revealed that, compared with wild-type animals, motor coordination was imp … More aired and the intraperitoneal injection of diazepam induced markedly reduced sedative and anti-anxiety effects in the mutant mice. These results indicate that PRIP is essential for the function of GABA_A receptors, especially in response to the agents acting on a γ2 subunit. Furthermore, we have examined the role for PRIP, which binds and inactivates PP1,in facilitating GABA_A receptor phospho-dependent regulation, using PRIP^<-/-> mice. In wild-type animals, robust phosphorylation and functional modulation of GABA_A receptors containing β3 subunits by cAMP-dependent protein kinase was evident, which was diminished in PRIP^<-/-> mice. PRIP^<-/-> mice exhibited enhanced PP1 activity compared to controls. Furthermore, PRIP was able to interact directly with GABA_A receptor p subunits, and moreover, these proteins were found to be PP1 substrates. Finally, phosphorylation of PRIP on threonine 94 facilitated the dissociation of PP1/PRIP complexes, providing a local mechanism for the activation of PP1. Together, these results suggest an essential role for PRIP in controlling GABAA receptor activity, via regulating subunit phosphorylation and thereby the efficacy of neuronal inhibition mediated by these receptors. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Mizoguchi, Y.et al.: "A rapid increase in the total number of cell-surface functional GABA_A receptors induced by BDNF in rat visual cortex."The Journal of Biological Chemistry. 278. 44097-44102 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hidaka, K.et al.: "The importance to chondrocyte differentiation of changes in expression of the multiple inositol polyphosphate phosphatase"Experimantal Cell Research. 290. 254-264 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi-Yanaga, F.et al.: "Dictyosterium differentiation-inducung factor-3 activates glycogen synthase kinase-3β and degrades cyclin D1 in mammalian cells"The Journal of Biological Chemistry. 278. 9663-9670 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanematsu, T.et al.: "Role of the PLC-related, Catalytically inactive protein p130 in GABA_A receptor function"EMBO Journal. 21. 1004-1011 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uji, A.et al.: "Molecules interacting with PRIP-2, a novel Ins(1,4,5)P_3 binding protein type 2 -Comparison with PRIP-1-"Life Sciences. 72. 443-453 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizoguchi, Y. et al.: "A rapid increase in the total number of cell-surface functional GABAA receptors induced by BDNF in rat visual cortex."The Journal of Biological Chemistry. 278. 44097-44102 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hidaka, K. et al.: "The importance to chondrocyte differentiation of changes in expression of the multiple inositol polyphosphate phosphatase"Experimental Cell Research. 290. 254-264 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi-Yanaga, F. et al.: "Dictyosterium differentiation-inducung factor-3 activates glycogen synthase kinase-3b and degrades cyclin D1 in mammalian cells"The Journal of Biological Chemistry. 278. 9663-9670

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"The EMBO Journal. 21. 1004-1011 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uji, A.et al.: "Molecules interacting with PRIP-2,A hovel Ins(1,4,5)_3 binding protein type 2"Life Sciences. 72. 443-453 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizoguchi, Y.et al.: "A rapid increase in the total number of cell-surface functional GABA_A receptors induced by BDNF in rat visual cortex"The Journal of Biological Chemistry. 278. 44097-44102 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hidaka, K.et al.: "The importance to chondrocyte differentiation of changes in expression of the multiple inositol polyphosphate phosphatase"Experimantal Cell Research. 290. 254-264 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takahashi-Yanaga, F.et al.: "Dictyosterium diffrentiation-inducung factor-3 activates glycogen synthase kinase-3b and degrades cyclin D1 in mammaliancells"The Journal of Biological Chemistry. 278. 9663-9670 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanematsu, T. et al.: "Role of the PLC-related, catalytically inactive protein p130 in GABA_A receptor function"EMBO Journal. 21. 1004-1011 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sandra, F. et al.: "TNF inhibited the apoptosis by activation of Akt serine/threonine kinase in the human head and neck squamous cell carcinoma"Cellular Signalling. 14. 771-778 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sandra, F. et al.: "Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFkB-mediated cell survival"Carcinogenesis. 23. 2031-2041 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uji, A.et al.: "Molecules interacting with PRIP-2, a novel Ins(1,4,5)P_3 binding protein type 2"Life Sciences. 72. 443-453 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kim, JH. et al.: "Phospholipase D2 directly interacts with aldolase via its PH domain"Biochemistry. 41. 3414-3421 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takahashi-Yanagi, F. et al.: "Dictyosterium differentiation-inducung factor-3 activates glycogen synthase kinase-3b and degrades cyclin D1 in mammalian cells"Journal of Biological Chemistry. (In press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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