Zhuravliova E, Barbakadze T, Natsvlishvili N, Mikeladze D G
Laboratory of Neurochemistry, Institute of Physiology 14 Gotua Street, Tbilisi 0160, Georgia.
Neurochem Int. 2007 Jun;50(7-8):976-82. doi: 10.1016/j.neuint.2006.09.015. Epub 2006 Nov 7.
The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides of agonist/coagonist sites, other modulator sites, including butyrophenone site may regulate the N-methyl-D-aspartate receptor. It has been shown that haloperidol, an antipsychotic neuroleptic drug, interacts with the NR2B subunit of NMDA receptor and inhibits NMDA response in neuronal cells. We found that NMDA receptor was co-immunoprecipitated by anti-Ras antibody and this complex, beside NR2 subunit of NMDA receptor contained haloperidol-binding proteins, nNOS and Ras-GRF. Furthermore, we have shown that haloperidol induces neurotoxicity of neuronal cells via NMDA receptor complex, accompanied by dissociation of Ras-GRF from membranes and activation of c-Jun-kinase. Inclusion of insulin prevented relocalization of Ras-GRF and subsequent neuronal death. Haloperidol-induced dissociation of Ras-GRF leads to inhibition of membrane-bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way. Our results suggest that haloperidol induces neuronal cell death by the interaction with NMDA receptor, but through the alternative from glutamate excitotoxicity signaling pathway.
N-甲基-D-天冬氨酸（NMDA）受体被认为在广泛的神经系统功能中起重要作用，包括神经元迁移、突触形成、学习和记忆。此外，它还参与了多种急性和慢性神经疾病中发生的兴奋性毒性神经元细胞死亡。除了激动剂/协同激动剂位点外，其他调节位点，包括丁酰苯位点，可能调节N-甲基-D-天冬氨酸受体。已经表明，抗精神病神经安定药物氟哌啶醇与NMDA受体的NR2B亚基相互作用，并抑制神经元细胞中的NMDA反应。我们发现NMDA受体被抗Ras抗体共免疫沉淀，并且这个复合物，除了NMDA受体的NR2亚基外，还包含氟哌啶醇结合蛋白、神经元型一氧化氮合酶（nNOS）和Ras鸟嘌呤核苷酸释放因子（Ras-GRF）。此外，我们已经表明，氟哌啶醇通过NMDA受体复合物诱导神经元细胞的神经毒性，伴随着Ras-GRF从膜上解离和c-Jun激酶的激活。加入胰岛素可防止Ras-GRF重新定位和随后的神经元死亡。氟哌啶醇诱导的Ras-GRF解离导致膜结合形式的Ras蛋白受到抑制，并改变下游调节因子的活性，从而通过线粒体途径引发凋亡过程。我们的结果表明，氟哌啶醇通过与NMDA受体相互作用诱导神经元细胞死亡，但通过谷氨酸兴奋性毒性信号通路的替代途径。
