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Papers of the Week

Papers: 23 May 2020 - 29 May 2020

Animal Studies, Pharmacology/Drug Development

2020 May 26

Proc Natl Acad Sci U S A

In vivo mapping of a GPCR interactome using knockin mice.


Degrandmaison J, Abdallah K, Blais V, Génier S, Lalumière M-P, Bergeron F, Cahill CM, Boulter J, Lavoie CL, Parent J-L, Gendron L
Proc Natl Acad Sci U S A. 2020 May 26.
PMID: 32457152.


With over 30% of current medications targeting this family of proteins, G-protein-coupled receptors (GPCRs) remain invaluable therapeutic targets. However, due to their unique physicochemical properties, their low abundance, and the lack of highly specific antibodies, GPCRs are still challenging to study in vivo. To overcome these limitations, we combined here transgenic mouse models and proteomic analyses in order to resolve the interactome of the δ-opioid receptor (DOPr) in its native in vivo environment. Given its analgesic properties and milder undesired effects than most clinically prescribed opioids, DOPr is a promising alternative therapeutic target for chronic pain management. However, the molecular and cellular mechanisms regulating its signaling and trafficking remain poorly characterized. We thus performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses on brain homogenates of our newly generated knockin mouse expressing a FLAG-tagged version of DOPr and revealed several endogenous DOPr interactors involved in protein folding, trafficking, and signal transduction. The interactions with a few identified partners such as VPS41, ARF6, Rabaptin-5, and Rab10 were validated. We report an approach to characterize in vivo interacting proteins of GPCRs, the largest family of membrane receptors with crucial implications in virtually all physiological systems.