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Analysis of intracellular signaling cascades mediated by receptor activation and protein phosphorylation in neostriatal

Research Project

Project/Area Number 10680727
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionKurume Unuviersity

Principal Investigator

NISHI Akinori  Kurume university, Dept of Physiology, Assistant Professor, 医学部, 講師 (50228144)

Co-Investigator(Kenkyū-buntansha) HIGACHI Hideho  Kurume university, Dept of Physiology, Professor, 医学部, 教授 (10098907)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsstriatum / dopamine / phosphorylation / DARPP-32 / protein phosphatase-1
Research Abstract

DARPP-32, a dopamine-and cAMP-regulated phosphoprotein of Mr 32 kDa, is a cytosolic protein that is selectively enriched in medium-sized spiny neurons in neostriatum. DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) at Thr34 residue, converting it into a potent inhibitor of protein phosphatase (PP) -1. Dopamine stimulates the phosphotylation of DARPP-32 and regulates the functions of ion channels and sodium pump and the excitability of neostriatal neurons by inhibiting PP-1. We studied the mechanisms of the regulation of DARPP-32 phosphorylation by various neurotransmitters and intracellular signaling systems, and obtained the following results.
1. Regulation of DARPP-32 phosphorylation by acethylcholine : Calbachol, non-selective cholinergic agonist, stimulates the phosphorylation of DARPP-32 at Thr34 in neostriatal neurons. The effect of calbachol was mediated through the activation of muscarinic receptors. Isoform of muscarinic receptors involved in the regulation of … More DARPP-32 phosphorylation, M1 or M4, is under investigation.
2. Regulation of DARPP-32 dephosphorylation : Phosph-Thr34 DARPP-32 is dephosphorylated by both calcineurin and PP-2A in neostriatal neurons. These two phosphatases act synergistically to maintain a low level of phospho-Thr34 DARPP-32.
3. Phosphorylation of DARPP-32 by cyclin-dependent protein kinase 5 (cdk5): DARPP-l32 at Thr75 is phosphorylated by cdk5/p35 complex in neostriatal neurons. phosphorylated form of DARPP-32 at Thr75 functions as an inhibitor of PKA in vitro and in neostriatal neurons.
4. Regulation of DARPP-32 phosphorylation at. Thr75 by PKA : Stimulation of PKA by forskolin, cAMP analogue or dopamine D1 agonist, SKF81297, reduced the level of phospho-Thr75 DARPP-32 in neostriatal neurons, resulting in the removal of the inhibition of PKA and further activation of PKA. Thus, the signaling cascade mediated by Thr75 phosphorylation functions as a positive feedback system for PKN/phospho-Thr34 DARPP-32/PP-1 and PEA/PKA substrate cascades. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Bibb JA et al.: "Phosphorylation of DARPP-32 by cdk5 modulates dopamine signalling in neurons"Nature. 402. 669-671 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishi A et al.: "Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons"J. Neurochem.. 72. 2015-2021 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishi A et al.: "Requirement for DARPP-32 in mediating effect of dopamine D2 receptor activation"Eur. J. Neurosci.. 11. 2589-2592 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishi A et al.: "Regulation of Na^+, K^+-ATPase isoforms in rat neostriatum by dopamine and protein kinase C"J. Neurochem.. 73. 1492-1501 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fienberg AA et al.: "DARPP-32, regulator of the efficacy of dopaminergic neurotransmission"Science. 281. 838-842 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Greengard P et al.: "The DARPP-32/protein phophatase-1 cascade : a model for signal integration"Brain Research Brain Research Reviews. 26. 274-284 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 西 昭徳: "ドーパミンによって制御される線条体蛋白質DARPP-32 -プロテインホスファターゼ1抑制蛋白質としての役割-"蛋白質核酸酵素. 43(12). 2172-2181 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 1. Fienberg AA, Hiroi N, Mermelstein P, Song W-J, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller D, Cole D, Corbett R, Haile C, Cooper D, Onn SP, Grace AA, Ouimet C, White FJ, Hyman SE, Surmeier DJ, Girault JA, Nestler E and Greengard P: "DARPP-32, regulator of the efficacy of dopaminergic neurotransmission"Science. 218. 838-842 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akinori, Nishi: "Role of DARPP-32 in dopamine signal transduction in the striatum"Tanpakushitsu Kakusan Koso. 43. 102-111 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Greengard P, Nairn AC, Girault J-A, Ouimet CC, Snyder GL, Fisone G, Allen PB, Fienberg A and Nishi A: "The DARPP-32/protein phophatase-1 cascade : a model for signal integration"Brain Res. Rev.. 26. 274-284 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Niisi A, Snyder Gli, Fienberg AA, Fisone G, Aperia A, Nairn AC, and Greengard P: "Requirement for DARPP-32 in mediating- effect of dopamine D2 receptor activation."Eur. J. Neurosci.. 11. 2589-2592 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishi A, Fisone G, Snyder GL, Dulubova I, Aperia A, Nairn AC, and Greengard P: "Regulation of NaィイD1+ィエD1, KィイD1+ィエD1-ATPase isoforms in rat. neostriatum by dopamine and protein kinase C"J. Neurochem. 43. 1492-1501 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishi A, Snyder GL, Nairn AC and Greengard P: "Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation. in neostriatal neurons"J. Neurochem. 72. 2015-2021 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai L-H, Kwon YT, Girault J-A, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC and Greengard P: "Phosphorylation of DARPP-32 by cdk5 modulates dopamine signalling in neurons."Nature. 402. 669-671 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Bibb JA et al.: "Phosphorylation of DARPP-32 by cdk5 modulates dopamine signalling in neurons."Nature. 402. 669-671 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishi A et al.: "Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons."J.Neurochem.. 72. 2015-2021 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishi A et al.: "Requirement for DARPP-32 in mediating effect of dopamine D2 receptor activation."Eur.J.Neurosci.. 11. 2589-2592 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishi A et al.: "Regulation of Na^+,K^+-ATPase isoforms in rat neostriatum by dopamine and protein kinase C."J.Neurochem.. 73. 1492-1501 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fienberg AA et al.: "DARPP-32,regulator of the efficacy of dopaminergic neurotransmission"Science. 281. 838-842 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Greengard P et al.: "The DARPP-32/protein phophatase-1 cascade: a model for signal integration"Brain Research Brain Research Reviews. 26. 274-284 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西 昭徳: "ドーパミンによって制御される線条体蛋白質DARPP-32-プロテインホスファターゼ1抑制蛋白質としての役割-"蛋白質核酸酵素. 43(12). 2172-2181 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishi A et al.: "Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons" Journal of Neurochemistry. 72(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fienberg AA et al.: "DARPP-32,regulator of the efficacy of dopaminergic neurotransmission" Science. 281. 838-842 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Greengard P et al.: "The DARPP-32/protein phophatase-1 cascade: a model for signal integration" Brain Research Brain Research Reviews. 26. 274-284 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 西 昭徳: "ドーパミンによって制御される線条体蛋白質DARPP-32 -プロテインホスファターゼ1抑制蛋白質としての役割-" 蛋白質核酸酵素. 43(12). 2172-2181 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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