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Analysis of the NMDA receptor-PDZ containing complexes as the drug targets

含NMDA受体-PDZ复合物作为药物靶点的分析

基本信息

批准号：
16590194
负责人：
YAMADA Yasue
金额：
$ 2.18万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590194/
关键词：
NMDA receptor PSD-95 GKAP PDZ PKC Src oocyte oocyte MAGUKs

项目摘要

We characterized the complex of NMDA receptor and PSD-95 using Xenopus oocyte expression system.1.We examined the effects of PSD-95 and GKAP (guanylate kinase associated protein) on four different subtypes of the NMDA receptor. The complex of PSD-95 and GKAP potentiated the channel activity of NR1/NR2B, and NR1/NR2C, but not of NR1/NR2A and NR1/NR2D. The inhibitions of PKC-mediated potentiation of the channel activity of NR1/NR2A and NR1/NR2B were not influenced by co-expressing GKAP. These results indicate that PSD-95 and GKAP differently modulate the channel activity of four subtypes of the NMDA receptor.2.SAP102, which is the member of MAGUKs family and PDZ containing protein, potentiated the basal channel activity of the NR1/NR2A and NR1/NR2B receptors. SAP102 inhibited the potentiation of the NR1/NR2A and NR1/NR2B channel activity induced by PKC. SAP102 also inhibited the Src-mediated potentiation of NR1/NR2A channels. Thus, SAP102 showed the similar effects to PSD-95 on NR1/NR2A-subtype NMDA receptor channels. The extent of the modulation by SAP102 was, however, lesser than that by PSD-95. These results indicate that the MAGUKs family modulates the NMDA receptor in a different manner.3.We examined the effect of MK-801 and ketamine on oocytes expressing NR1/NR2A receptor and co-expressing with PSD-95. The NR1/NR2A receptor-PSD-95 complex showed the higher sensitivity to MK-801 and ketamine than the receptor alone. These results indicate that the receptor-PDZ-containing protein complex is a potential target to develop a new drug.

我们利用非洲爪蟾卵母细胞表达系统对NMDA受体和PSD-95的复合物进行了表征。1.我们检测了PSD-95和GKAP（鸟苷酸激酶相关蛋白）对NMDA受体四种不同亚型的影响。 PSD-95 和 GKAP 的复合物增强了 NR1/NR2B 和 NR1/NR2C 的通道活性，但不增强 NR1/NR2A 和 NR1/NR2D 的通道活性。 PKC 介导的 NR1/NR2A 和 NR1/NR2B 通道活性增强的抑制不受共表达 GKAP 的影响。这些结果表明PSD-95和GKAP对NMDA受体四种亚型的通道活性有不同的调节作用。2.SAP102是MAGUKs家族的成员，含有PDZ蛋白，可增强NR1/NR2A和NR1/NR2B受体的基础通道活性。 SAP102 抑制 PKC 诱导的 NR1/NR2A 和 NR1/NR2B 通道活性增强。 SAP102 还抑制 Src 介导的 NR1/NR2A 通道增强。因此，SAP102 对 NR1/NR2A 亚型 NMDA 受体通道表现出与 PSD-95 类似的作用。然而，SAP102 的调节程度小于 PSD-95。这些结果表明MAGUKs家族以不同的方式调节NMDA受体。3.我们检测了MK-801和氯胺酮对表达NR1/NR2A受体并与PSD-95共表达的卵母细胞的影响。 NR1/NR2A 受体-PSD-95 复合物对 MK-801 和氯胺酮比单独的受体表现出更高的敏感性。这些结果表明含有受体-PDZ的蛋白质复合物是开发新药的潜在靶点。