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  In vivo brain GPCR signaling elucidated by phosphoproteomics

Liu, J. J., Sharma, K., Zangrandi, L., Chen, C., Humphrey, S. J., Chiu, Y.-T., et al. (2018). In vivo brain GPCR signaling elucidated by phosphoproteomics. Science, 360(6395): eaao4927. doi:10.1126/science.aao4927.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-7108-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-7109-5
Genre: Journal Article

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© 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License.

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 Creators:
Liu, Jeffrey J.1, Author              
Sharma, Kirti1, Author              
Zangrandi, Luca2, Author
Chen, Chongguang2, Author
Humphrey, Sean J.1, Author              
Chiu, Yi-Ting2, Author
Spetea, Mariana2, Author
Liu-Chen, Lee-Yuan2, Author
Schwarzer, Christoph2, Author
Mann, Matthias1, Author              
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              

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Free keywords: KAPPA-OPIOID RECEPTOR; CAMP-REGULATED PHOSPHOPROTEIN; PROTEIN-COUPLED RECEPTORS; SYNAPTIC PLASTICITY; 6'-GUANIDINONALTRINDOLE 6'-GNTI; COMPUTATIONAL PLATFORM; RAT HIPPOCAMPUS; HIGHLY POTENT; AGONIST; PHOSPHORYLATIONScience & Technology - Other Topics;
 Abstract: A systems view of G protein-coupled receptor (GPCR) signaling in its native environment is central to the development of GPCR therapeutics with fewer side effects. Using the kappa opioid receptor (KOR) as a model, we employed high-throughput phosphoproteomics to investigate signaling induced by structurally diverse agonists in five mouse brain regions. Quantification of 50,000 different phosphosites provided a systems view of KOR in vivo signaling, revealing novel mechanisms of drug action. Thus, we discovered enrichment of the mechanistic target of rapamycin (mTOR) pathway by U-50,488H, an agonist causing aversion, which is a typical KOR-mediated side effect. Consequently, mTOR inhibition during KOR activation abolished aversion while preserving beneficial antinociceptive and anticonvulsant effects. Our results establish high-throughput phosphoproteomics as a general strategy to investigate GPCR in vivo signaling, enabling prediction and modulation of behavioral outcomes.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Published online
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: ISI: 000436040600035
DOI: 10.1126/science.aao4927
 Degree: -

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Title: Science
  Other : Science
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Association for the Advancement of Science
Pages: - Volume / Issue: 360 (6395) Sequence Number: eaao4927 Start / End Page: - Identifier: ISSN: 0036-8075
CoNE: https://pure.mpg.de/cone/journals/resource/991042748276600_1