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

NMDA受体对长时程增强（LTP）的诱导至关重要，LTP被认为在记忆和学习的突触可塑性中起着关键作用。NMDA受体通常与突触后密度蛋白（包括PSD-95）形成复合物。mal -2和α-肌动蛋白。目前尚不清楚这些蛋白质如何调节NMDA受体的通道活性。本研究通过将PSD-95 CRNA注入表达NMDA受体的非洲爪蟾卵母细胞，研究了PSD-95对NMDA受体4种ε1/ζ1、ε2/ζ1、ε3/ζ1和ε4/ζ1亚型的影响。我们还研究了另一种PDZ蛋白MALS-2对NMDA受体通道活性的影响。PSD-95抑制蛋白激酶C （PKC）介导的ε1/ζ1和ε2/ζ1增强和src介导的ε1/ζ1增强。据报道，胰岛素能增强ε1/ζ1、ε2/ζ1、ε3/ζ1和ε4/ζ1的电流。PSD-95的共表达消除了所有四种亚型的胰岛素诱导增强。MALS-2不能消除PKC、Src和胰岛素对通道的增强作用。我们证明突触后密度蛋白，如PSD-95和MALS-2，可以功能性地调节NMDA受体的通道活性。

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.