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DOI | 10.1126/science.aao4927 |
In vivo brain GPCR signaling elucidated by phosphoproteomics | |
Liu, Jeffrey J.1; Sharma, Kirti1; Zangrandi, Luca2; Chen, Chongguang3,4; Humphrey, Sean J.1; Chiu, Yi-Ting3,4; Spetea, Mariana5,6; Liu-Chen, Lee-Yuan3,4; Schwarzer, Christoph2; Mann, Matthias1,7 | |
2018-06-22 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2018 |
卷号 | 360期号:6395页码:1314-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Germany; Austria; USA; Denmark |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000436040600035 |
WOS关键词 | KAPPA-OPIOID RECEPTOR ; CAMP-REGULATED PHOSPHOPROTEIN ; PROTEIN-COUPLED RECEPTORS ; SYNAPTIC PLASTICITY ; 6' ; -GUANIDINONALTRINDOLE 6' ; -GNTI ; COMPUTATIONAL PLATFORM ; RAT HIPPOCAMPUS ; HIGHLY POTENT ; AGONIST ; PHOSPHORYLATION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/198946 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany; 2.Med Univ Innsbruck, Dept Pharmacol, A-6020 Innsbruck, Austria; 3.Temple Univ, Lewis Katz Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA; 4.Temple Univ, Lewis Katz Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA; 5.Univ Innsbruck, Inst Pharm, Dept Pharmaceut Chem, A-6020 Innsbruck, Austria; 6.Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria; 7.Univ Copenhagen, Novo Nordisk Fdn, Fac Hlth Sci, Ctr Prot Res, DK-2200 Copenhagen, Denmark |
推荐引用方式 GB/T 7714 | Liu, Jeffrey J.,Sharma, Kirti,Zangrandi, Luca,et al. In vivo brain GPCR signaling elucidated by phosphoproteomics[J]. SCIENCE,2018,360(6395):1314-+. |
APA | Liu, Jeffrey J..,Sharma, Kirti.,Zangrandi, Luca.,Chen, Chongguang.,Humphrey, Sean J..,...&Mann, Matthias.(2018).In vivo brain GPCR signaling elucidated by phosphoproteomics.SCIENCE,360(6395),1314-+. |
MLA | Liu, Jeffrey J.,et al."In vivo brain GPCR signaling elucidated by phosphoproteomics".SCIENCE 360.6395(2018):1314-+. |
条目包含的文件 | 条目无相关文件。 |
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