Effects of metabotropic glutamate mGlu5 receptor antagonist on tyrosine phosphorylation of NMDA receptor subunits and cell death in the hippocampus after brain ischemia in rats
Effects of metabotropic glutamate mGlu5 receptor antagonist on tyrosine phosphorylation of NMDA receptor subunits and cell death in the hippocampus after brain ischemia in rats
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DOI：
10.1016/j.neulet.2012.09.035
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发表时间：
2012-11
影响因子：
2.5
通讯作者：
N. Takagi;S. Besshoh;T. Marunouchi;S. Takeo;K. Tanonaka
中科院分区：
文献类型：
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作者：
N. Takagi;S. Besshoh;T. Marunouchi;S. Takeo;K. Tanonaka
N-甲基-D-天冬氨酸（NMDA）受体的酪氨酸磷酸化似乎与受体离子通道的调节有关。本研究旨在观察代谢型谷氨酸mGlu 5受体拮抗剂对短暂性全脑缺血后海马CA 1区NMDA受体亚单位酪氨酸磷酸化和细胞死亡的影响，并探讨其作用机制。用mGlu 5受体拮抗剂预处理可减少短暂缺血后第3天海马CA 1区的细胞死亡。短暂性缺血增加了NMDA受体亚基的酪氨酸磷酸化，这是Src家族酪氨酸激酶的主要靶点。因此，我们研究了短暂缺血后拮抗剂对NMDA受体亚基酪氨酸磷酸化的影响。酪氨酸磷酸化的NR 2A亚基，但不是NR 2B的一个，被抑制的mGlu 5受体拮抗剂。拮抗剂的施用也减弱了再灌注后Src活性形式的量的增加。我们进一步证明，给予Src家族激酶抑制剂可以预防海马CA 1区的细胞死亡，并减弱再灌注后NMDA受体亚基酪氨酸磷酸化的增加。这些结果表明，短暂缺血后海马CA 1区的mGlu 5受体参与激活Src和随后的NMDA受体亚基的酪氨酸磷酸化，这一行动可能有助于改变NMDA受体的性质，并可能与致病事件导致神经元细胞死亡。
Tyrosine phosphorylation of the N-methyl-D-aspartate (NMDA) receptor appears to be associated with the regulation of the receptor's ion channel. This study focused on the effect of a metabotropic glutamate mGlu5 receptor antagonist on tyrosine phosphorylation of NMDA receptor subunits and cell death in the hippocampal CA1 region after transient global ischemia and sought to explore their mechanisms. Pretreatment with the mGlu5 receptor antagonist reduced cell death in the hippocampal CA1 region on day 3 after the transient ischemia. Transient ischemia increased the tyrosine phosphorylation of NMDA receptor subunits, which are a major target of Src family tyrosine kinases. Therefore, we investigated the effect of the antagonist on tyrosine phosphorylation of the NMDA receptor subunits after transient ischemia. Tyrosine phosphorylation of the NR2A subunit, but not that of the NR2B one, was inhibited by the mGlu5 receptor antagonist. The administration of the antagonist also attenuated the increase in the amount of active form of Src after the reperfusion. We further demonstrated that the administration of a Src-family kinase inhibitor prevented cell death in the hippocampal CA1 region and attenuated the increase in the tyrosine phosphorylation of the NMDA receptor subunits after the reperfusion. These findings suggest that mGlu5 receptor in the hippocampal CA1 region after transient ischemia is involved in the activation of Src and subsequent tyrosine phosphorylation of NMDA receptor subunits, which actions may contribute to alterations of properties of the NMDA receptor and may be related to pathogenic events leading to neuronal cell death.