抗精神病药物对NMDA受体功能的细胞内调节
Intracellular modulation of NMDA receptor function by antipsychotic drugs.
作者信息
Leveque J C, Macías W, Rajadhyaksha A, Carlson R R, Barczak A, Kang S, Li X M, Coyle J T, Huganir R L, Heckers S, Konradi C
机构信息
Molecular and Developmental Neuroscience Laboratory and Department of Psychiatry, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, USA.
出版信息
J Neurosci. 2000 Jun 1;20(11):4011-20. doi: 10.1523/JNEUROSCI.20-11-04011.2000.
The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.
本研究探讨了抗精神病药物与N-甲基-D-天冬氨酸（NMDA）受体之间的功能相互作用。我们发现，传统抗精神病药物氟哌啶醇和非典型抗精神病药物氯氮平均通过对NMDA受体的细胞内调节来介导基因表达，尽管程度不同。在原代纹状体培养物中获得的数据表明，氟哌啶醇激活的细胞内信号转导途径——环磷酸腺苷（cAMP）途径，导致NMDA受体NR1亚型在（897）位丝氨酸处磷酸化。同样，在体内实验中，氟哌啶醇处理也显示可增加大鼠体内（897）位丝氨酸-NR1的磷酸化。将（896）位丝氨酸和（897）位丝氨酸突变为丙氨酸可阻止这两个位点的磷酸化，从而抑制cAMP介导的基因表达。我们得出结论，抗精神病药物能够通过细胞内信号转导机制调节NMDA受体功能。这种对NMDA活性的促进作用对抗精神病药物介导的基因表达是必要的，并且可能有助于抗精神病药物治疗的疗效以及副作用。
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