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The Molecular Mechanism Underlying Morphine-Induced Akt Activation: Roles of Protein Phosphatases and Reactive Oxygen Species

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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 Ser473, 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 KATP 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.

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Acknowledgments

This study was supported by Grant 2007136 from Bureau of Education, Hebei Province, China.

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Authors and Affiliations

  1. Heart Institute, Hebei United University, Tangshan, Hebei, 063000, China

    Jingman Xu, Wei Tian, Jing Guo, Yulan Jin & Jinkun Xi

  2. Department of Surgery, Worker’s Hospital, Tangshan, Hebei, 063000, China

    Xiaolong Ma

  3. Department of Internal Medicine, University Hospital, Hebei United University, Tangshan, Hebei, 063000, China

    Qiuyan Shi

  4. Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Zhelong Xu

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  1. Jingman Xu
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Correspondence to Zhelong Xu.

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Jingman Xu, Wei Tian, and Xiaolong Ma contributed equally to this study.

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Xu, J., Tian, W., Ma, X. et al. The Molecular Mechanism Underlying Morphine-Induced Akt Activation: Roles of Protein Phosphatases and Reactive Oxygen Species. Cell Biochem Biophys 61, 303–311 (2011). https://doi.org/10.1007/s12013-011-9213-5

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