Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Neurosci Lett. 2012 Nov 14;530(1):91-6. doi: 10.1016/j.neulet.2012.09.035. Epub 2012 Sep 27.
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.
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。本研究集中于代谢型谷氨酸 mGlu5 受体拮抗剂对短暂全脑缺血后海马 CA1 区 NMDA 受体亚基酪氨酸磷酸化和细胞死亡的影响，并试图探讨其机制。mGlu5 受体拮抗剂预处理可减少短暂缺血后第 3 天海马 CA1 区的细胞死亡。短暂缺血增加了 NMDA 受体亚基的酪氨酸磷酸化，而 NMDA 受体亚基是 Src 家族酪氨酸激酶的主要靶标。因此，我们研究了拮抗剂对短暂缺血后 NMDA 受体亚基酪氨酸磷酸化的影响。NR2A 亚基的酪氨酸磷酸化，但 NR2B 亚基的酪氨酸磷酸化不受 mGlu5 受体拮抗剂的抑制。拮抗剂的给药也减弱了再灌注后 Src 的活性形式的增加。我们进一步表明，Src 家族激酶抑制剂的给药可防止海马 CA1 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。这些发现表明，短暂缺血后海马 CA1 区的 mGlu5 受体参与了 Src 的激活以及随后 NMDA 受体亚基的酪氨酸磷酸化，这些作用可能导致 NMDA 受体特性的改变，并可能与导致神经元细胞死亡的致病事件有关。
