Molecular mechanisums of regulation of NMDA receptor by post-synaptic density proteins

突触后密度蛋白调控NMDA受体的分子机制

• 批准号: 12680755
• 负责人: YAMADA Yasue
• 金额: $ 2.3万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680755/
• 关键词: NMPA recptor; PSD-95; MALS-2; PDZ proteins; Xenopus oocyte; PKC; Src; insulin; PDZ protein; グルタミン酸受容体; Xenopus oocyte; 二電極膜電位固定法; チロシンリン酸化酵素; プロテインキナーゼC; 亜鉛

The NMDA receptors is essential for the induction of long term potentiation (LTP) which is thought to plays a key role in synaptic plasticity underlying memory and learning. The NMDA receptor usually makes the complex with post-synaptic density proteins including PSD-95. MALS-2 and α-actinin. It is unknown how those proteins regulate the channel activity of the NMDA receptor. In this study, we examined the effects of PSD-95 on four )ε1/ζ1, ε2/ζ1, ε3/ζ1 and ε4/ζ1) subtypes of the NMDA receptor by injection of PSD-95 CRNA into Xenopus oocytes expressing the receptors. We also examined the effects of another PDZ protein, MALS-2, on the channel activity of the NMDA receptor. PSD-95 inhibited the protein kinase C (PKC) - mediated potentiation ofε1/ζ1 and ε2/ζ1 and the Src-mediated potentiation of ε1/ζ1. It has been reported that insulin potentiates the currents of the ε1/ζ1, ε2/ζ1, ε3/ζ1 and ε4/ζ1. Co-expressing of PSD-95 eliminated the insulin-induced potentiation of all four subtypes. MALS-2 dose not eliminate the potentiation of the channels by PKC, Src and insulin. We demonstrated that post-synaptic density proteins, like PSD-95 and MALS-2, functionally modulate the channel activity of NMDA receptor.

NMDA 受体对于诱导长时程增强 (LTP) 至关重要，LTP 被认为在记忆和学习的突触可塑性中发挥着关键作用，NMDA 受体通常与包括 PSD-95 在内的突触后密度蛋白形成复合物。 -2 和 α-肌动蛋白。这些蛋白质如何调节 NMDA 受体的通道活性尚不清楚。在这项研究中，我们检查了 PSD-95 对 4 个 )ε1/δ1 的影响。通过将 PSD-95 CRNA 注射到表达受体的爪蟾卵母细胞中，我们还检测了另一种 PDZ 蛋白 MALS-2 对 NMDA 受体通道活性的影响。 NMDA 受体抑制蛋白激酶 C (PKC) 介导的 ε1/δ1 和 ε2/δ1 增强作用。 Src 介导的 ε1/δ1 增强 据报道，胰岛素增强了 PSD-95 的 ε1/δ1、ε2/δ1、ε3/δ1 和 ε4/δ1 的电流，消除了胰岛素诱导的 ε1/δ1 增强。所有四种亚型均未消除 PKC、Src 和胰岛素对通道的增强作用。 PSD-95 和 MALS-2 等蛋白质可在功能上调节 NMDA 受体的通道活性。

项目成果

Zhai,J.: "Cardiac-specific overexpression of a superinhibitory pentameric phospholamban mutant enhances inhibition of cardiac function in vivo"J Biol Chem. 275. 10538-10544 (2000)

Zhai, J.：“超抑制性五聚受磷蛋白突变体的心脏特异性过度表达增强了体内心脏功能的抑制”J Biol Chem。

Haghighi.K., et al.: "Superinhibition of sarcoplasmic reticulum function by phospholamban induces cardiac contractile failure."Journal of Biological Chemistry. 276. 24145-24152 (2001)

Haghighi.K. 等人：“受磷素对肌浆网功能的超级抑制会导致心脏收缩衰竭。”《生物化学杂志》。

Kimura,Yoshihiro: "Reconstitution of the cytoplasmic interaction between phospholamban and Ca2^+-ATPase of cardiac sarcoplasmic reticulum"Mol. Pharmacol. 61 (3). 667-673 (2002)

Kimura，Yoshihiro：“心脏肌浆网受磷蛋白和Ca2+-ATP酶之间细胞质相互作用的重建”Mol。

Zhai, J., et al.: "Cardiac-specific ovcrcxpression of a superinhibitory pentameric phospholamban mutant enhances inhibition of cardiac function in vivo"Journal of Biological Chemistry. 275. 10538-10544 (2000)

Zhai, J., et al.：“超抑制性五聚受磷蛋白突变体的心脏特异性表达增强了体内心脏功能的抑制”生物化学杂志。

Yasue Yamada.: "PSD-95 climinates src-induced potentiation of NRI/NR2A-subtype NMDA receptor channels and reduces high-affinity zinc inhibition"Journal of Neurochemistry. (in press). (2002)

Yasue Yamada.：“PSD-95 使 src 诱导的 NRI/NR2A 亚型 NMDA 受体通道增强，并减少高亲和力锌抑制”《神经化学杂志》。