Alterations in subunit expression, composition, and phosphorylation of striatal <i>N</i>-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease

作     者：Dunah, AW Wang, YH Yasuda, RP Kameyama, K Huganir, RL Wolfe, BB Standaert, DG 

作者机构：Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Harvard Univ Sch Med Boston MA USA Georgetown Univ Sch Med Dept Pharmacol Washington DC USA Johns Hopkins Univ Med Ctr Dept Neurosci Baltimore MD 21218 USA 

出 版 物：《MOLECULAR PHARMACOLOGY》 (分子药理学)

年 卷 期：2000年第57卷第2期

页      面：342-352页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：NINDS NIH HHS [NS31579  NS2830  NS34361] Funding Source: Medline 

主　　题：抗震颤麻痹药/药理学 细胞膜/药物作用 细胞膜/代谢 纹状体/药物作用 纹状体/代谢 疾病模型 动物 左旋多巴/药理学 神经元/药物作用 神经元/代谢 羟多巴胺 帕金森病 继发性/化学诱导 帕金森病 继发性/代谢 磷酰化 大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/药物作用 受体 N-甲基-D-天冬氨酸/代谢 动物 男(雄)性 大鼠 

摘      要：Recent evidence has linked striatal N-methyl-D-aspartate (NMDA) receptor function to the adverse effects of long-term dopaminergic treatment in Parkinson s disease. We have studied the abundance, composition, and phosphorylation of NMDA receptor subunits (NRs) in the rat 6-hydroxydopamine lesion model of parkinsonism. In lesioned striatum, the abundance of NR1 and NR2B in striatal membranes was decreased to 68 +/- 3.2 and 62 +/- 4.4%, respectively, relative to the unlesioned striata, whereas the abundance of NR2A was unchanged. Coimmunoprecipitation of NMDA receptors under nondenaturing conditions revealed that these changes reflected a selective depletion of receptors composed of NR1/NR2B, without alteration in receptors composed of NR1/NR2A. However, the abundance and composition of striatal NMDA receptors in extracts containing both cytoplasmic and membrane proteins were not altered in lesioned rats, suggesting that the changes in the membrane fraction resulted from intracellular redistribution of receptors. The phosphorylation of NR1 protein at serine 890 and serine 896, but not at serine 897, and the tyrosine phosphorylation of NR2B but not NR2A were decreased in the membrane fraction of the lesioned striatum. Chronic treatment of lesioned rats with L-dopa normalized the alterations in the abundance and subunit composition of the NMDA receptors in striatal membranes, and produced striking hyperphosphorylation, both of NR1 at serine residues, and NR2A and NR2B at tyrosine residues. These findings suggest that the adverse motor effects of chronic L-dopa therapy may result from alterations in regulatory phosphorylation sites on NMDA receptors.