In vivo brain GPCR signaling elucidated by phosphoproteomics
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Science (New York, N.Y.) |
Vol/bind | 360 |
Udgave nummer | 6395 |
Sider (fra-til) | 1-11 |
ISSN | 0036-8075 |
DOI | |
Status | Udgivet - 2018 |
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527112/pdf/nihms-1014127.pdf
Forlagets udgivne version
ID: 198717121