In vivo brain GPCR signaling elucidated by phosphoproteomics

TY - JOUR

T1 - In vivo brain GPCR signaling elucidated by phosphoproteomics

AU - Liu, Jeffrey J

AU - Sharma, Kirti

AU - Zangrandi, Luca

AU - Chen, Chongguang

AU - Humphrey, Sean J

AU - Chiu, Yi-Ting

AU - Spetea, Mariana

AU - Liu-Chen, Lee-Yuan

AU - Schwarzer, Christoph

AU - Mann, Matthias

N1 - Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1126/science.aao4927

DO - 10.1126/science.aao4927

M3 - Journal article

C2 - 29930108

SN - 0036-8075

VL - 360

SP - 1

EP - 11

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6395

ER -