Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins
Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins
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DOI：
10.1046/j.1471-4159.2003.02293.x
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发表时间：
2004-04-01
影响因子：
4.7
通讯作者：
Inui, M
中科院分区：
文献类型：
--
作者：
Iwamoto, T;Yamada, Y;Inui, M
含有PSD-95/Dlg/ZO-1（PDZ）结构域的蛋白质MALS和PSD-95定位于突触后密度并结合NMDA受体的NR 2亚基的COOH末端。使用爪蟾卵母细胞表达系统比较了MALS-2和PSD-95对NMDA受体通道活性的影响。MALS-2和PSD-95均增加NR 1-NR 2B受体对L-谷氨酸的电流响应。相反，NR 1-NR 2A受体的电流响应被PSD-95而不是被MALS-2增加。MALS-2对蛋白激酶C增强NR 1-NR 2A或NR 1-NR 2B通道活性或Src介导的增强NR 1-NR 2A活性没有影响，而PSD-95几乎完全抑制这些蛋白激酶的作用。MALS-2和PSD-95嵌合体的构建揭示了PSD-95对蛋白激酶C介导的NR 1-NR 2A和NR 1-NR 2B通道活性增强的抑制作用的前两个PDZ结构域和两个NH 2-末端半胱氨酸残基是必需的。PSD-95的三个PDZ结构域中的第二个是其抑制Src介导的NR 1-NR 2A活性增强所必需的。这些结果表明NR 1-NR 2A和NR 1-NR 2B受体受MALS-2和PSD-95的不同调节，PSD-95对这些受体的类似调节作用是通过不同的机制实现的。
The PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins MALS and PSD-95 localize to post-synaptic densities and bind the COOH-termini of NR2 subunits of the NMDA receptor. The effects of MALS-2 and PSD-95 on the channel activity of NMDA receptors were compared using the Xenopus oocyte expression system. Both MALS-2 and PSD-95 increased the current response of the NR1-NR2B receptor to L-glutamate. In contrast, the current response of the NR1-NR2A receptor was increased by PSD-95 but not by MALS-2. MALS-2 had no effect either on the potentiation of NR1-NR2A or NR1-NR2B channel activity by protein kinase C, or on Src-mediated potentiation of NR1-NR2A activity, whereas PSD-95 almost completely inhibited the effects of these protein kinases. Construction of chimeras of MALS-2 and PSD-95 revealed that the first two PDZ domains and two NH2-terminal cysteine residues are essential for the inhibitory effects of PSD-95 on protein kinase C-mediated potentiation of NR1-NR2A and NR1-NR2B channel activity, respectively. The second of the three PDZ domains of PSD-95 was required for its inhibition of Src-mediated potentiation of NR1-NR2A activity. These results indicate that the NR1-NR2A and NR1-NR2B receptors are modulated differentially by MALS-2 and PSD-95, and that similar regulatory effects of PSD-95 on these receptors are achieved by distinct mechanisms.