In vivo brain GPCR signaling elucidated by phosphoproteomics

Jeffrey J Liu; Kirti Sharma; Luca Zangrandi; Chongguang Chen; Sean J Humphrey; Yi-Ting Chiu; Mariana Spetea; Lee-Yuan Liu-Chen; Christoph Schwarzer; Matthias Mann

doi:10.1126/science.aao4927

In vivo brain GPCR signaling elucidated by phosphoproteomics

Jeffrey J Liu, Kirti Sharma, Luca Zangrandi, Chongguang Chen, Sean J Humphrey, Yi-Ting Chiu, Mariana Spetea, Lee-Yuan Liu-Chen, Christoph Schwarzer, Matthias Mann

54 Citations (Scopus)

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.

Original language	English
Journal	Science (New York, N.Y.)
Volume	360
Issue number	6395
Pages (from-to)	1-11
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aao4927
Publication status	Published - 2018

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title = "In vivo brain GPCR signaling elucidated by phosphoproteomics",

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.",

author = "Liu, {Jeffrey J} and Kirti Sharma and Luca Zangrandi and Chongguang Chen and Humphrey, {Sean J} and Yi-Ting Chiu and Mariana Spetea and Lee-Yuan Liu-Chen and Christoph Schwarzer and Matthias Mann",

note = "Copyright {\textcopyright} 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2018",

doi = "10.1126/science.aao4927",

language = "English",

volume = "360",

pages = "1--11",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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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

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

JF - Science

IS - 6395

ER -

In vivo brain GPCR signaling elucidated by phosphoproteomics

Abstract

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