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Science. 2018 Jun 22;360(6395). pii: eaao4927. doi: 10.1126/science.aao4927.

In vivo brain GPCR signaling elucidated by phosphoproteomics.

Author information

1
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
2
Department of Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
3
Center for Substance Abuse Research and Department of Pharmacology, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
4
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
5
Department of Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria. mmann@biochem.mpg.de schwarzer.christoph@i-med.ac.at.
6
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. mmann@biochem.mpg.de schwarzer.christoph@i-med.ac.at.
7
Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

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.

PMID:
29930108
DOI:
10.1126/science.aao4927
[Indexed for MEDLINE]

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