Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Eur J Pharmacol. 2010 Oct 10;644(1-3):96-100. doi: 10.1016/j.ejphar.2010.07.026. Epub 2010 Jul 24.
Phosphorylation of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the regulation of the receptor's ion channel. The contribution of metabotropic glutamate receptors to the NMDA receptor function after brain ischemia remains to be determined. Presently we investigated the effects of an antagonist of the metabotropic glutamate mGlu5 receptor on cell death and serine phosphorylation of the NR1 subunit of the NMDA receptor in the hippocampal CA1 region after transient global ischemia and sought to explore the mechanisms involved. Phosphorylation of serine residues at 890 and 896 of NR1 was increased predominantly in the deoxycholate (DOC)-insoluble fraction after transient global ischemia in rats; and the increase in the phosphorylation of S890, but not that of S896, of NR1 in this fraction was attenuated by the mGlu5 receptor antagonist. The administration of this antagonist also reduced the increase in the amount of protein kinase C (PKC)gamma, but not that of PKCalpha, in the DOC-insoluble fraction. The results suggest that the mGlu5 receptor in the hippocampal CA1 region is involved in the phosphorylation of S890 of NR1 subunit via PKCgamma following transient ischemia. As treatment with the mGlu5 receptor antagonist reduced cell death in the hippocampal CA1 region on day 3 after the start of the reperfusion, these changes in intracellular signaling through mGlu5 receptor may be linked to the pathogenesis of cerebral ischemia.
N-甲基-D-天冬氨酸（NMDA）受体 NR1 亚基的磷酸化被认为参与了受体离子通道的调节。代谢型谷氨酸受体在脑缺血后对 NMDA 受体功能的贡献仍有待确定。目前，我们研究了一种代谢型谷氨酸 mGlu5 受体拮抗剂对短暂全脑缺血后海马 CA1 区细胞死亡和 NMDA 受体 NR1 亚基丝氨酸磷酸化的影响，并试图探讨其中涉及的机制。在大鼠短暂全脑缺血后，NR1 的丝氨酸 890 和 896 残基的磷酸化主要增加于脱氧胆酸钠（DOC）不溶性部分；并且这种部分中 NR1 的 S890 磷酸化的增加（但不是 S896 的磷酸化）被 mGlu5 受体拮抗剂减弱。该拮抗剂的给药还减少了 DOC 不溶性部分中蛋白激酶 C（PKC）γ的增加，但 PKCalpha 的增加没有减少。结果表明，海马 CA1 区的 mGlu5 受体通过短暂缺血后的 PKCγ参与了 NR1 亚基 S890 的磷酸化。由于 mGlu5 受体拮抗剂在再灌注开始后第 3 天减少了海马 CA1 区的细胞死亡，因此通过 mGlu5 受体的这种细胞内信号转导变化可能与脑缺血的发病机制有关。
