Pharmacological and phosphoproteomic approaches to roles of protein kinase C in 
kappa opioid receptor-mediated effects in mice.

Liu, Jeffrey J.; Chiu, Yi-Ting; Chen, Chongguang; Huang, Peng; Mann, Matthias; Liu-Chen, Lee-Yuan

doi:10.1016/j.neuropharm.2020.108324

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Pharmacological and phosphoproteomic approaches to roles of protein kinase C in kappa opioid receptor-mediated effects in mice.

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Liu, Jeffrey J.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann, Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Liu, J. J., Chiu, Y.-T., Chen, C., Huang, P., Mann, M., & Liu-Chen, L.-Y. (2020). Pharmacological and phosphoproteomic approaches to roles of protein kinase C in kappa opioid receptor-mediated effects in mice. Neuropharmacology, 181: 108324. doi:10.1016/j.neuropharm.2020.108324.

Zitierlink: https://hdl.handle.net/21.11116/0000-0007-817E-A

Zusammenfassung

Kappa opioid receptor (KOR) agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as non-addictive anti-pruritic and analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the beneficial antinociceptive and antipruritic effects of KOR agonists, but attenuated the adverse condition placed aversion (CPA), sedation, and motor incoordination in mice. Using a large-scale mass spectrometry-based phosphoproteomics of KOR-mediated signaling in the mouse brain, we observed PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways at 5 min; stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1 at 30 min. We further demonstrated that inhibition of CB1 attenuated KOR-mediated CPA. Our results demonstrated the feasibility of in vivo biochemical dissection of signaling pathways that lead to side effects. Copyright © 2020. Published by Elsevier Ltd.