Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, People's Republic of China.
PLoS One. 2013 Jun 11;8(6):e65187. doi: 10.1371/journal.pone.0065187. Print 2013.
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.
先前，我们已经证实了丙泊酚通过磷酸肌醇 3-激酶（PI3K）介导的急性（24 小时）后处理发挥神经保护作用。我们还发现丙泊酚后处理产生了长期的神经保护作用，并抑制了 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体 GluR2 亚基在大脑中动脉闭塞（MCAO）后 28 天的内吞作用。然而，PI3K 与丙泊酚后处理中 AMPA 受体 GluR2 亚基转运之间的关系尚未被探索。在这里，我们发现丙泊酚后处理促进了 PI3K 与 AMPA 受体 GluR2 亚基 C 末端的结合，并在短暂 MCAO 后 1 天内形成复合物。有趣的是，在缺血后 1 天，后处理大鼠的海马中观察到 PI3K 活性增强，而在同一组中，AMPAR GluR2 亚基内吞作用的减少持续至 28 天。PI3K 选择性拮抗剂wortmannin 的给药抑制了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 内吞作用的抑制。总之，我们的数据表明 PI3K 在调节丙泊酚后处理诱导的长期神经保护中起着关键作用。此外，这种作用是通过第一天激活 PI3K 和形成 PI3K-AMPA 受体 GluR2 复合物来建立的，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抑制了 GluR2 亚基的内吞作用。
