Signal transduction mechanisms mediated via heterotrimeric G proteins implicated in pathophysiology of affective disorders
Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants |
|Research Institution||Department of Psychiatry, Saitama Medical School |
ODAGAKI Yuji Saitama Medical School, Department of Psychiatry, Associate Professor, 医学部, 助教授 (10221160)
|Project Period (FY)
2001 – 2004
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)
|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|
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)
Research Products (13 results)