Murotomi Kazutoshi, Takagi Norio, Mizutani Reiko, Honda Taka-aki, Ono Megumi, Takeo Satoshi, Tanonaka Kouichi
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
J Neurochem. 2010 Sep;114(6):1711-9. doi: 10.1111/j.1471-4159.2010.06882.x. Epub 2010 Aug 19.
NADPH oxidase, which is activated by PKC and signaling via the NMDA receptor, is one of the crucial enzymes for superoxide production in the CNS. We showed earlier that the metabotropic glutamate receptor 1 (mGluR1) plays an important role in the activation of PKC and tyrosine phosphorylation of the NMDA receptor, which has been implicated in enhancement of the channel activity, after cerebral ischemia. In this study, we sought to determine the role of mGluR1 in the activation of NADPH oxidase and subsequent superoxide production after transient focal cerebral ischemia. The amounts of NADPH oxidase subunits in the membrane fraction were increased after the start of reperfusion. These changes were accompanied by increased NADPH oxidase activity followed by superoxide production. The administration of an mGluR1 antagonist attenuated NADPH oxidase activity, which was coincident with inhibition of superoxide production. We further showed that the increase in the amount of PKCδ, but not of PKCζ, as well as the increase in those of NADPH oxidase subunits, was attenuated by the mGluR1 antagonist. These results suggest that mGluR1 may be linked to the increase in NADPH oxidase activity that is mediated by PKCδ and subsequent superoxide production after cerebral ischemia.
NADPH氧化酶由蛋白激酶C（PKC）激活，并通过N-甲基-D-天冬氨酸（NMDA）受体进行信号传导，是中枢神经系统中产生超氧化物的关键酶之一。我们之前表明，代谢型谷氨酸受体1（mGluR1）在PKC的激活以及NMDA受体的酪氨酸磷酸化过程中发挥重要作用，而这与脑缺血后通道活性的增强有关。在本研究中，我们试图确定mGluR1在短暂性局灶性脑缺血后NADPH氧化酶激活及随后超氧化物产生过程中的作用。再灌注开始后，膜组分中NADPH氧化酶亚基的量增加。这些变化伴随着NADPH氧化酶活性的增加以及随后超氧化物的产生。给予mGluR1拮抗剂可减弱NADPH氧化酶活性，这与超氧化物产生的抑制相一致。我们进一步表明，mGluR1拮抗剂可减弱PKCδ而非PKCζ量的增加以及NADPH氧化酶亚基量的增加。这些结果表明，mGluR1可能与脑缺血后由PKCδ介导的NADPH氧化酶活性增加以及随后的超氧化物产生有关。
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