title: The molecular mechanism underlying morphine-induced Akt activation: roles of protein phosphatases and reactive oxygen species.
abstract: Although Akt is reported to play a role in morphine's cardioprotection, little is known about the mechanism underlying morphine-induced Akt activation. This study aimed to define the molecular mechanism underlying morphine-induced Akt activation and to determine if the mechanism contributes to the protective effect of morphine on ischemia/reperfusion injury. In cardiac H9c2 cells, morphine increased Akt phosphorylation at Ser(473), indicating that morphine upregulates Akt activity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a major regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling, was not involved in the action of morphine on Akt activity. Morphine decreased the activity of PP2A, a major protein Ser/Thr phosphatase, and inhibition of PP2A with okadaic acid (OA) mimicked the effect of morphine on Akt activity. The effects of morphine on PP2A and Akt activities were inhibited by the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)glycine (MPG) and the mitochondrial K(ATP) channel closer 5-hydroxydecanoate (5HD). In support, morphine could produce ROS and this was reversed by 5HD. Finally, the cardioprotective effect of morphine on ischemia-reperfusion injury was mimicked by OA but was suppressed by 5HD or MPG, indicating that protein phosphatases and ROS are involved in morphine's protection. In conclusion, morphine upregulates Akt activity by inactivating protein Ser/Thr phosphatases via ROS, which may contribute to the cardioprotective effect of morphine.
authors.affiliation: Heart Institute, Hebei United University, Tangshan, Hebei, China.
authors.forename: Jingman
authors.initials: J
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Shi
authors.forename: Yulan
authors.initials: Y
authors.lastname: Jin
authors.forename: Jinkun
authors.initials: J
authors.lastname: Xi
authors.forename: Zhelong
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D009020:Morphine / Q000494:pharmacology*; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D009020:Morphine; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase