The early stage formation of PI3K-AMPAR GluR2 subunit complex facilitates the long term neuroprotection induced by propofol post-conditioning in rats.
The early stage formation of PI3K-AMPAR GluR2 subunit complex facilitates the long term neuroprotection induced by propofol post-conditioning in rats.
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PI3K-AMPAR GluR2 亚基复合物的早期形成促进异丙酚后处理对大鼠的长期神经保护作用
DOI：
10.1371/journal.pone.0065187
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhu A
中科院分区：
文献类型：
--
作者：
Wang H;Wang G;Wang C;Wei Y;Wen Z;Wang C;Zhu A
此前，我们已经证明磷酸肌醇 3 激酶 (PI3K) 介导丙泊酚诱导的急性（24 小时）后调节神经保护作用。我们还发现，异丙酚后处理可产生长期的神经保护作用，并抑制 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体 GluR2 亚基的内化，直至大脑中动脉闭塞 (MCAO) 后 28 天。然而，异丙酚后处理中 PI3K 与 AMPA 受体 GluR2 亚基运输之间的关系从未被探索过。在这里，我们发现丙泊酚后处理促进 PI3K 与 AMPA 受体 GluR2 亚基 C 端的结合，并在短暂 MCAO 后 1 天内形成复合物。有趣的是，在缺血后第 1 天，在后处理大鼠的海马中观察到 PI3K 活性增强，而在同一组中长达 28 天发现 AMPA 受体 GluR2 亚基内化减少。给予PI3K选择性拮抗剂渥曼青霉素可抑制空间学习记忆的改善和齿状回神经发生的增加直至缺血后28天。它还逆转了丙泊酚后处理诱导的 AMPA 受体 GluR2 内化抑制。总之，我们的数据表明 PI3K 在调节异丙酚后处理诱导的长期神经保护中发挥着关键作用。此外，这一作用是通过PI3K的第一天激活和PI3K-AMPA受体GluR2复合物的形成而建立的，从而稳定了突触后AMPA受体的结构，并在丙泊酚后处理的早期阶段抑制了GluR2亚基的内化。
Previously, we have shown that the phosphoinositide-3-kinase (PI3K) mediated acute (24 h) post-conditioning neuroprotection induced by propofol. We also found that propofol post-conditioning produced long term neuroprotection and inhibited the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit up to 28 days post middle cerebral artery occlusion (MCAO). However, the relationship between PI3K with AMPA receptor GluR2 subunit trafficking in propofol post-conditioning has never been explored. Here we showed that propofol post-conditioning promoted the binding of PI3K to the C-terminal of AMPA receptor GluR2 subunit and formed a complex within 1 day after transient MCAO. Interestingly, the enhanced activity of PI3K was observed in the hippocampus of post-conditioning rats at day 1 post ischemia, whereas the decrease of AMPA receptor GluR2 subunit internalization was found up to 28 days in the same group. Administration of PI3K selective antagonist wortmannin inhibited the improvement of spatial learning memory and the increase of neurogenesis in the dentate gyrus up to 28 days post ischemia. It also reversed the inhibition of AMPA receptor GluR2 internalization induced by propofol post-conditioning. Together, our data indicated the critical role of PI3K in regulating the long term neuroprotection induced by propofol post-conditioning. Moreover, this role was established by first day activation of PI3K and formation of PI3K-AMPA receptor GluR2 complex, thus stabilized the structure of postsnaptic AMPA receptor and inhibited the internalization of GluR2 subunit during the early stage of propofol post-conditioning.
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影响因子：
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