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Molecular mechanisms to amplify dopamine signaling in neostriatal neurons

Research Project

Project/Area Number 12680763
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionKurume University Scientifiv Research (C) (2)

Principal Investigator

NISHI Akinori  Kurume Univ. Sch. Of Med. Assistant Professor, 医学部, 教授 (50228144)

Co-Investigator(Kenkyū-buntansha) HIGASHI Hideho  Kurume Univ. Sch. of Med. Professor, 医学部, 講師 (10098907)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsstriatum / dopamine / intracclular signaling / phosphorylation / DARPP-32 / Cdk5 / 線条件
Research Abstract

DARPP-32 (Dopamine and cyclic AMP-Regulated Phospho-Protein, Mr 32 kDa) plays an obligatory role in most of the actions of dopamine. DARPP-32 is phosphorylated on Thr34 by cAMP-dependent protein kinase (PKA), resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP-i). When DARPP-32 is phosphorylated on Thr75 by cdk5, it becomes an inhibitor of PKA and thereby modulates dopaminergic signaling (Bibb et al., Nature 402 : 669-671, 1999). In this study, we investigated the regulation of DARPP-32 phosphorylation at Thr75 by dopamine. Using mOuse neostriatal slices, SKF8 1297, a D1 agonist, decreased the level of phospho-Thr75 DARPP-32 through a echanism involving PKA. Quinpirole, a D2 agonist, increased the level of phospho-Thr75 DARPP-32.
We have found, in striatal homogenates, that PP-2A plays a prominent role in the dephosphorylation of phospho-Thr75 DARPP-32.The ability of PKA to dephosphorylate phospho-Thr75 DARPP-32 might be explained either by an inhibition of cdk5 activity or by a stimulation of PP-2A activity. Forskolin decreased the level of phospho-Thr75 DARPP-32.This effect of forskolin was abolished in the presence of concentration of okadaic acid (1μM), which selectively inhibited PP-2A, but not in the presence of roscovitine, a selective inhibitor of cdk5.In addition, treatment of slices with forskolin did not alter cdk5 activities measured subsequently in homogenate. These data demonstrate that PKA dephosphorylates phospho-Thr75 DARPP-32, possibly by a mechanism involving the activation of PKA
2A. Together, these results indicate that via positive feedback mechanisms Cdk5 signaling and PKA signaling are mutually antagonistic.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Nishi A: "Amplification of dopaminergic signaling by a positive feedback loop"Proc.Nail.Acad.Sci.USA. 97. 12840-12845 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi E: "Phosphorylation of protein phosphatase-1 inhibitors, inhibitor-1 and DARPP-32, in renal medulla"Eur.J.Pharmacol.. 408. 107-116 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Bibb JA: "Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5"Nature. 410. 376-380 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Bibb JA: "Phosphorylation of Protein Phosphatase Inhibitor-1 by Cdk5"J.Biol.Chem.. 276. 14490-14497 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Liu F: "Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors"Proc.Natl.Acad.Sci.USA. 98. 11062-11068 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuyama S: "Neurotensin regulates DARPP-32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors"J.Neurochem.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi A: "Regulation of DARPP-32 dephosphorylation at PKA-and Cdk5-sites by NMDA and AMPA receptors : distinct roles of calcineurin and protein phosphatase-2A"J.Neurochem.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi A, Bibb JA, Snyder GL, Higashi H, NairnAC, Greengard P.: "Amplification of dopaminergic signaling by a positive feedback loop."Proc. Natl. Avad. Sci. USA. 97. 12840-12845 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Higuchi E, Nishi A, Higashi H, Ito Y, Kato H. /: "Phosphorylation of protein phosphatase- 1 inhibitors, inhibitor- 1 and DARPP-32, in renal medulla."Eur. J. Pharmacol.. 408. 107-116 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Bibb JA, Chen JS, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P.: "Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5."Nature. 410. 376-380 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Bibb JA, Nishi A, O'Callaghan JP, Ule J, Lan M, Snyder GL, Horiuchi A, Saito T, Hisanaga S, Czernik AJ, Nairn AC, Greengard P.: "Phosphorylation of Protein Phosphatase Inhibitor- 1 by Cdk5."J. Biol. Chem.. 276. 14490-14497 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Liu F, Ma X-H, Ule J, Bibb JA, Nishi A, DeMaggioAJ, Yan Z, Nairn AC, Greengard P.: "Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors."Proc. Natl. Avad. Sci. USA. 98. 11062-11068 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuyama S, Higashi H, Maeda H, Greengard P, NishiA.: "Neuroten/in regulates DARPP-32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine Dl-type receptors."J. Neurochem. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi A, Bibb JA, Matsuyama S, Hamada M, Higashi H, Nairn AC, Greengard P.: "Regulation of DARPP-32 dephosphorylation at PKA and Cdk5-sites by NMDA and AMPA receptors : distinct roles of calcineurin and protein phosphatase-2A."J. Neurochem. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nishi A: "Amplification of dopaminergic signaling by a positive feedback loop"Proc.Natl.Acad.Sci.USA. 97. 12840-12845 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Higuchi E: "Phosphorylation of protein phosphatase-1 inhibitors, inhibitor-1 and DARPP-32, in renal medulla"Eur.J.Pharmacol.. 408. 107-116 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Bibb JA: "Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5"Nature. 410. 376-380 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Bibb JA: "Phosphorylation of Protein Phosphatase Inhibitor-1 by Cdk5"J.Biol.Chem.. 276. 14490-14497 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Liu F: "Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors"Proc.Natl.Acad.Sci.USA. 98. 11062-11068 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsuyama S: "Neurotensin regulates DARPP-32 Thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors"J.Neurochem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nishi A: "Regulation of DARPP-32 dephosphorylation at PKA-and Cdk5-sites by NMDA and AMPA receptors : distinct roles of calcineurin and protein phosphatase-2A"J.Neurochem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Bibb JA et al.: "Cdk5 regulates action of chronic cocaine."Nature. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Bibb JA et al.: "Phosphorylation of Protein Phosphatase Inhibitor-1 by Cdk5."J.Biol.Chem.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishi A et al.: "Amplification of dopaminergic signaling by a positive feedback loop."Proc.Natl.Acad.Sci.USA. 97. 12840-12845 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Higuchi E et al.: "Phosphorylation of protein phosphatase inhibitors, inhibitor-1 and DARPP-32, in renal medulla."Eur.J.Pharmacol.. 408. 107-116 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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