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Signal transduction mechanisms mediated via heterotrimeric G proteins implicated in pathophysiology of affective disorders

Research Project

Project/Area Number 13671030
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionDepartment of Psychiatry, Saitama Medical School

Principal Investigator

ODAGAKI Yuji  Saitama Medical School, Department of Psychiatry, Associate Professor, 医学部, 助教授 (10221160)

Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2002: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsG protein / [^<35>S]GTPγS binding / serotonin receptors / dopamine receptors / antidepressants / antipsychotics / affective disorders / σ受容体 / 三量体G蛋白 / γ-Hydroxybutyric acid / Trazodone / シグマ受容体 / 非定型抗精神病薬 / 三量体G蛋白質 / γ-hydroxyburyrate
Research Abstract

Agonist-induced [^<35>S]GTPγS binding in rat brain membranes and culture cell membranes was measured to investigate functional coupling between the receptors and their coupled G proteins. The results are summarized as follows :
1. The putative neurotransmitter γ-hydroxybutyrate (GHB) was ineffective as a stimulator in [^<35>S]GTPγS binding assay in rat brain membranes. In contrast to GABA_B receptors, GHB receptors were not coupled to G proteins, at least G_<i/0>.
2. There were no stimulating effects of several sigma (s) ligands on [^<35>S]GTPγS binding in rat brain membranes, except for (+)-3-PPP. The stimulatory effect of (+)-3-PPP in rat striatal membranes was mediated by dopamine D_2 receptors, but not a receptors. It was concluded that σ receptors were not metabotropic ones which are coupled to G proteins.
3. In rat hippocampal membranes, 5-HT-stimulated [^<35>S]GTPγS binding was shown to be mediated by 5-HT_<1A> receptor subtype.
4. In rat cerebral cortical membranes, it was also demonstrated that 5-HT_<1A> receptors are involved in 5-HT-stimulated [^<35>S]GTPγS binding.
5. On the other hand, 5-HT-stimulated [^<35>S]GTPγS binding in rat striatal membranes was mediated through 5-HT_<1B> receptors.
6. It has been shown that the atypical antidepressant trazodone, and its active metabolite m-chlorophenylpiperazine (m-CPP) as well, behaves as a partial agonist at 5-HT_<1A> receptors in rat brain membranes and CHO cells expressing 5-HT_<1A> receptors. This effect may underlie the therapeutic efficacy of trazodone.
7. Several atypical antipsychotics such as clozapine were partial agonists at 5-HT_<1A> receptors in rat brain membranes. Among conventional antipsychotics, nemonapride was the most efficacious drug. These effects may be implicated in the clinical efficacy of these antipsychotics on negative symptoms.

Report

(5 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (13 results)

All 2005 2004 Other

All Journal Article (10 results) Book (2 results) Publications (1 results)

  • [Journal Article] Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT_<1A> receptors assessed by [^<35>S]GTPγS binding2005

    • Author(s)
      Yuji Odagaki
    • Journal Title

      Journal of Psychopharmacology 19

      Pages: 235-241

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lack of G protein-coupled sigma receptors in rat brain membranes : receptor-mediated high affinity GTPase activity and [^<35>S]GTPγS binding studies2005

    • Author(s)
      Yuji Odagaki
    • Journal Title

      Journal of Neural Transmission (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Detailed pharmacological characterization of 5-HT_<1A> receptor-mediated [^<35>S]GTPγS binding in rat hippocampal membranes2005

    • Author(s)
      Yuji Odagaki
    • Journal Title

      Journal of Pharmacological Sciences (印刷中)

    • NAID

      10025727986

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT_<1A> receptors assessed by [^<35>S]GTPγS binding2005

    • Author(s)
      Yuji Odagaki et al.
    • Journal Title

      Journal of Psychopharmacology 19

      Pages: 235-241

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Lack of G protein-coupled sigma receptors in rat brain membranes : receptor-mediated high affinity GTPase activity and [^<35>S]GTPγS binding studies2005

    • Author(s)
      Yuji Odagaki et al.
    • Journal Title

      Journal of Neural Transmission (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] γ-Hydroxybutyric acid, unlike γ-aminobutyric acid, does not stimulate G_i/_0 proteins in rat brain membranes2004

    • Author(s)
      Yuji Odagaki
    • Journal Title

      Basic and Clinical Pharmacology and Toxicology 94

      Pages: 89-98

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] γ-Hydroxybutyric acid, unlike γ-aminobutyric acid, does not stimulate G_i/G_0 proteins in rat brain membranes2004

    • Author(s)
      Yuji Odagaki et al.
    • Journal Title

      Basic and Clinical Pharmacology and Toxicology 94

      Pages: 89-98

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lack of G protein-coupled sigma receptors in rat brain membranes : receptor-mediated high affinity GTPase activity and [^<35>S]GTPγS binding studies

    • Author(s)
      Yuji Odagaki et al.
    • Journal Title

      Journal of Neural Transmission (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Detailed pharmacological characterization of 5-HT_<1A> receptor-mediated [^<35>S]GTPγS binding in rat hippocampal membranes

    • Author(s)
      Yuji Odagaki, Ryoichi Toyoshima
    • Journal Title

      Journal of Pharmacological Sciences (in press)

    • NAID

      10025727986

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transmembrane signal transduction via G proteins implicated in affective disorders

    • Author(s)
      Yuji Odagaki
    • Journal Title

      Focus on Bipolar Disorder Research (Nova Science publishers) (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Transmembrane signal transduction via G proteins implicated in affective disorders2005

    • Author(s)
      Yuji Odagaki
    • Publisher
      Focus on Bipolar Disorder Research(印刷中)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Focus on Bipolar Disorder Research

    • Author(s)
      Yuji Odagaki
    • Publisher
      (印刷中)
    • Related Report
      2004 Annual Research Report
  • [Publications] Yuji Odagaki: "γ-Hydroxybutyric acid, unlike γ-aminobutyric acid, does not stimulate G_i/G_o proteins in rat brain membranes"Basic and Clinical Pharmacology and Toxicology. 94. 89-98 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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