Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking
Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking
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DOI：
10.1523/jneurosci.0792-06.2006
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发表时间：
2006-04-26
影响因子：
5.3
通讯作者：
Dunah, AW
中科院分区：
文献类型：
--
作者：
Hallett, PJ;Spoelgen, R;Dunah, AW
纹状体中多巴胺能和多巴胺能传入之间的相互作用对于运动学习和运动调节是必不可少的。这些相互作用的一个重要机制是多巴胺通过D-1受体增强NMDA谷氨酸受体功能的能力。在这里，我们表明，在纹状体神经元，D-1受体激活导致快速贩运的NMDA受体亚基，增加NR 1和NR 2B亚基在树突，增强cocollustering这些亚基与突触后密度支架分子突触后密度-95，并增加表面表达。多巴胺D-1受体介导的NMDA受体运输被酪氨酸激酶抑制剂阻断。酪氨酸磷酸酶的阻断剂也诱导NMDA亚基运输，但这种作用是非选择性的，并改变NR 2A和NR 2B受体。此外，酪氨酸磷酸酶抑制导致酪氨酸磷酸化的NR 2B亚基沿着树突轴聚集。我们的研究结果表明，D-1受体激活可以加强纹状体NMDA亚基的功能，直接促进表面插入的受体复合物。这种作用受蛋白酪氨酸磷酸酶和酪氨酸激酶的相互作用调节。这些途径的修饰可能是帕金森病和其他基底神经节疾病的有用治疗靶点，其中纹状体NMDA受体的功能异常有助于疾病的症状。
Interactions between dopaminergic and glutamatergic afferents in the striatum are essential for motor learning and the regulation of movement. An important mechanism for these interactions is the ability of dopamine, through D-1 receptors, to potentiate NMDA glutamate receptor function. Here we show that, in striatal neurons, D-1 receptor activation leads to rapid trafficking of NMDA receptor subunits, with increased NR1 and NR2B subunits in dendrites, enhanced coclustering of these subunits with the postsynaptic density scaffolding molecule postsynaptic density-95, and increased surface expression. The dopamine D-1 receptor-mediated NMDA receptor trafficking is blocked by an inhibitor of tyrosine kinases. Blockers of tyrosine phosphatases also induce NMDA subunit trafficking, but this effect is nonselective and alters both NR2A- and NR2B-containing receptors. Furthermore, tyrosine phosphatase inhibition leads to the clustering of tyrosine-phosphorylated NR2B subunit along dendritic shafts. Our findings reveal that D-1 receptor activation can potentiate striatal NMDA subunit function by directly promoting the surface insertion of the receptor complexes. This effect is regulated by the reciprocal actions of protein tyrosine phosphatases and tyrosine kinases. Modification of these pathways may be a useful therapeutic target for Parkinson's disease and other basal ganglia disorders in which abnormal function of striatal NMDA receptors contributes to the symptoms of the diseases.