| Project/Area Number |
15500272
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Kurume University |
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Principal Investigator |
FUKUI Ryuichi Kurume University, Sch of Med, Dept of Physiology, Research Associate, 医学部, 助手 (00309791)
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| Co-Investigator(Kenkyū-buntansha) |
NISHI Akinori Kurume University, Sch of Med, Dept of Physiology, Associate Professor, 医学部, 助教授 (50228144)
SOTOGAKU Naoki Kurume University, Sch of Med, Dept of Physiology, Research Associate, 医学部, 助手 (60368884)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | striatum / dopamine / GABA_B receptor / intracellular signaling / DARPP-32 / protein phosphorylation |
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| Research Abstract |
Dopamine plays a central role in the regulation of psychomotor function in the brain. Many of the actions of dopamine are mediated through signal transduction pathways that involve DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa). When DARPP-32 is phosphorylated on Thr34, it is converted into a potent inhibitor of protein phosphatase-1(PP-1), and thereby controls the phosphorylation state and activity of many downstream physiological effectors. Since actions of neurotransmitters in neostriatal neurons are integrated to DARPP-32 phosphorylation, DARPP-32 is suitable for the analysis of the convergence of intracellular signal. In this study, we investigated the role of GABAB receptors in the dopamine/DARPP-32 signaling cascade using mouse neostriatal slices.Activation of GABA_B receptors with its agonist, baclofen (200 μM), resulted in the stimulation of Thr34 (PKA-site) and Ser97 (CK2-site) phosphorylation, but did not affect Thr75(Cdk5-site)or Ser130 (CK2-site) phosphorylation. Since neurotensin stimulates the release of dopamine and activates dopamine D1 receptor/PKA/DARPP-32 Thr34 signaling, the role of GABA_B receptors in neurotensin-mediated DARPP-32 phosphorylation was examined. Interestingly, both a GABA_B receptor agonist, baclofen(200 μM), and a GABA_B receptor antagonist, hydroxysaclofen (100μM), potentiated neurotensin-mediated DARPP-32 Thr34 phosphorylation. These results demonstrate that GABA_B receptors have both stimulatory and inhibitory effects on dopamine signaling in the striatum by acting at multiple sites in pre- and post-synaptic neurons. We are conducting further studies to clarify the GABA_B receptor signaling cascades.
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