| Project/Area Number |
10680727
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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 Unuviersity |
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Principal Investigator |
NISHI Akinori Kurume university, Dept of Physiology, Assistant Professor, 医学部, 講師 (50228144)
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| Co-Investigator(Kenkyū-buntansha) |
HIGACHI Hideho Kurume university, Dept of Physiology, Professor, 医学部, 教授 (10098907)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | striatum / dopamine / phosphorylation / DARPP-32 / protein phosphatase-1 |
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| Research Abstract |
DARPP-32, a dopamine-and cAMP-regulated phosphoprotein of Mr 32 kDa, is a cytosolic protein that is selectively enriched in medium-sized spiny neurons in neostriatum. DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) at Thr34 residue, converting it into a potent inhibitor of protein phosphatase (PP) -1. Dopamine stimulates the phosphotylation of DARPP-32 and regulates the functions of ion channels and sodium pump and the excitability of neostriatal neurons by inhibiting PP-1. We studied the mechanisms of the regulation of DARPP-32 phosphorylation by various neurotransmitters and intracellular signaling systems, and obtained the following results.
1. Regulation of DARPP-32 phosphorylation by acethylcholine : Calbachol, non-selective cholinergic agonist, stimulates the phosphorylation of DARPP-32 at Thr34 in neostriatal neurons. The effect of calbachol was mediated through the activation of muscarinic receptors. Isoform of muscarinic receptors involved in the regulation of
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DARPP-32 phosphorylation, M1 or M4, is under investigation.
2. Regulation of DARPP-32 dephosphorylation : Phosph-Thr34 DARPP-32 is dephosphorylated by both calcineurin and PP-2A in neostriatal neurons. These two phosphatases act synergistically to maintain a low level of phospho-Thr34 DARPP-32.
3. Phosphorylation of DARPP-32 by cyclin-dependent protein kinase 5 (cdk5): DARPP-l32 at Thr75 is phosphorylated by cdk5/p35 complex in neostriatal neurons. phosphorylated form of DARPP-32 at Thr75 functions as an inhibitor of PKA in vitro and in neostriatal neurons.
4. Regulation of DARPP-32 phosphorylation at. Thr75 by PKA : Stimulation of PKA by forskolin, cAMP analogue or dopamine D1 agonist, SKF81297, reduced the level of phospho-Thr75 DARPP-32 in neostriatal neurons, resulting in the removal of the inhibition of PKA and further activation of PKA. Thus, the signaling cascade mediated by Thr75 phosphorylation functions as a positive feedback system for PKN/phospho-Thr34 DARPP-32/PP-1 and PEA/PKA substrate cascades. Less
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