title: The early stage formation of PI3K-AMPAR GluR2 subunit complex facilitates the long term neuroprotection induced by propofol post-conditioning in rats.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, People's Republic of China. wanghy819@hotmail.com
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
authors.forename: Chenxu
authors.initials: C
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhiting
authors.initials: Z
authors.lastname: Wen
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Ai
authors.initials: A
authors.lastname: Zhu
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002539:Cerebral Arterial Diseases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015742:Propofol / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D006993:Hypnotics and Sedatives; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015742:Propofol; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D000077191:Wortmannin