1999 Fiscal Year Final Research Report Summary
Analysis of intracellular signaling cascades mediated by receptor activation and protein phosphorylation in neostriatal
| 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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| 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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[Publications] 1. Fienberg AA, Hiroi N, Mermelstein P, Song W-J, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller D, Cole D, Corbett R, Haile C, Cooper D, Onn SP, Grace AA, Ouimet C, White FJ, Hyman SE, Surmeier DJ, Girault JA, Nestler E and Greengard P: "DARPP-32, regulator of the efficacy of dopaminergic neurotransmission"Science. 218. 838-842 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai L-H, Kwon YT, Girault J-A, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC and Greengard P: "Phosphorylation of DARPP-32 by cdk5 modulates dopamine signalling in neurons."Nature. 402. 669-671 (1999)
Description
「研究成果報告書概要(欧文)」より
