Signal transduction mechanisms mediated via heterotrimeric G proteins implicated in pathophysiology of affective disorders
| Project/Area Number |
13671030
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Department of Psychiatry, Saitama Medical School |
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Principal Investigator |
ODAGAKI Yuji Saitama Medical School, Department of Psychiatry, Associate Professor, 医学部, 助教授 (10221160)
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| Project Period (FY) |
2001 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | G 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 |
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| 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.
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Report
(5 results)
Research Products
(13 results)
