Yamada Yasue, Iwamoto Takashi, Watanabe Yoshifumi, Sobue Kenji, Inui Makoto
Department of Pharmacology, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan.
J Neurochem. 2002 May;81(4):758-64. doi: 10.1046/j.1471-4159.2002.00886.x.
The channel activity of NMDA receptors is regulated by phosphorylation by protein kinases and by interaction with other proteins. Recombinant NR1/NR2A subtype NMDA receptor channels are potentiated by the protein tyrosine kinase Src, an effect which is mediated by a reduction in the high-affinity, voltage-independent Zn(2+) inhibition. However, it has been reported that Src-induced potentiation of NMDA receptor currents in hippocampus neurons is not mediated by a reduction in Zn(2+) inhibition. The post-synaptic density protein PSD-95 interacts with the C-terminus of NR2 subunits of the NMDA receptor. Here we demonstrate that PSD-95 eliminates the Src-induced potentiation of NR1/NR2A channels expressed in oocytes and reduces the sensitivity of the channels to Zn(2+). Our results reveal that the absence of Src-induced potentiation of PSD-95-coupled NR1/NR2A channels is not to due to the reduced sensitivity of these channels to Zn(2+). These results indicate that PSD-95 functionally modulates NR1/NR2A channels and explain why Src-induced potentiation of NMDA receptor currents in hippocampus neurons is not mediated by a reduction in Zn(2+) inhibition.
NMDA受体的通道活性受蛋白激酶磷酸化作用以及与其他蛋白相互作用的调节。重组的NR1/NR2A亚型NMDA受体通道可被蛋白酪氨酸激酶Src增强，该效应由高亲和力、电压非依赖性的Zn(2+)抑制作用的减弱介导。然而，有报道称Src诱导的海马神经元NMDA受体电流增强并非由Zn(2+)抑制作用的减弱介导。突触后致密蛋白PSD-95与NMDA受体NR2亚基的C末端相互作用。在此我们证明，PSD-95消除了Src诱导的卵母细胞中表达的NR1/NR2A通道的增强作用，并降低了通道对Zn(2+)的敏感性。我们的结果表明，缺乏Src诱导的与PSD-95偶联的NR1/NR2A通道增强作用并非由于这些通道对Zn(2+)的敏感性降低。这些结果表明，PSD-95在功能上调节NR1/NR2A通道，并解释了为什么Src诱导的海马神经元NMDA受体电流增强并非由Zn(2+)抑制作用的减弱介导。
