Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation
Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation
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DOI：
10.1073/pnas.032654599
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发表时间：
2002-02-05
影响因子：
11.1
通讯作者：
Aperia, A
中科院分区：
文献类型：
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作者：
Scott, L;Kruse, MS;Aperia, A
谷氨酸通过激活 N-甲基-D-天冬氨酸 (NMDA) 受体，改变多巴胺 D1 和 D2 受体信号传导之间的平衡，但造成这种作用的机制尚不清楚。我们在这里报告，使用大鼠新纹状体神经元原代培养物的免疫细胞化学，NMDA 受体的激活将 D1 受体从细胞内部募集到质膜，同时对 D2 受体的分布没有影响。 D1 受体集中在棘中，如与鬼笔环肽标记的肌动蛋白丝共定位所示。通过在无钙培养基中培养细胞，NMDA 对 D1 受体的作用被消除，并被钙离子载体洛霉素模拟。通过亚细胞分级证实 D1 受体从细胞内部募集到膜上。经 NMDA 预处理的细胞膜中多巴胺敏感的腺苷酸环化酶活性增加，证明了招募的 D1 受体具有功能。这些结果为神经元中 G 蛋白偶联受体的调节募集提供了证据，为 NMDA 对多巴胺信号传导的影响提供了细胞生物学基础，并调和了精神分裂症的相互冲突的高多巴胺能和低谷氨酸能假说。
Glutamate, by activating N-methyl-D-aspartate (NMDA) receptors, alters the balance between dopamine D1 and D2 receptor signaling, but the mechanism responsible for this effect has not been known. We report here, using immunocytochemistry of primary cultures of rat neostriatal neurons, that activation of NMDA receptors recruits D1 receptors from the interior of the cell to the plasma membrane while having no effect on the distribution of D2 receptors. The D1 receptors were concentrated in spines as shown by colocalization with phalloidin-labeled actin filaments. The effect of NMDA on D1 receptors was abolished by incubation of cells in calcium-free medium and was mimicked by the calcium ionophore lonomycin. Recruitment of D1 receptors from the interior of the cell to the membrane was confirmed by subcellular fractionation. The recruited D1 receptors were functional as demonstrated by an increase in dopamine-sensitive adenylyl cyclase activity in membranes derived from cells that had been pretreated with NMDA. These results provide evidence for regulated recruitment of a G protein-coupled receptor in neurons, provide a cell biological basis for the effect of NMDA on dopamine signaling, and reconcile the conflicting hyperdopaminergic and hypoglutamatergic hypotheses of schizophrenia.