Genetic behavioral screen identifies an orphan anti-opioid system | Zendy

Dandan Wang | Zendy; Hannah M. Stoveken | Zendy; Stefano Zucca | Zendy; Maria Dao | Zendy; Cesare Orlandi | Zendy; Chenghui Song | Zendy; Ikuo Masuho | Zendy; Caitlin Johnston | Zendy; Karla J. Opperman | Zendy; Andrew C. Giles | Zendy; Matthew S. Gill | Zendy; Erik A. Lundquist | Zendy; Brock Grill | Zendy; Kirill A. Martemyanov | Zendy

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Genetic behavioral screen identifies an orphan anti-opioid system

Author(s) -

Dandan Wang,

Hannah M. Stoveken,

Stefano Zucca,

Maria Dao,

Cesare Orlandi,

Chenghui Song,

Ikuo Masuho,

Caitlin Johnston,

Karla J. Opperman,

Andrew C. Giles,

Matthew S. Gill,

Erik A. Lundquist,

Brock Grill,

Kirill A. Martemyanov

Publication year - 2019

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aau2078

Subject(s) - heterotrimeric g protein , opioid , μ opioid receptor , opioid receptor , g protein , pharmacology , chemical genetics , caenorhabditis elegans , neuroscience , g protein coupled receptor , signal transduction , biology , receptor , microbiology and biotechnology , genetics , gene , small molecule

Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans , we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide-binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein-coupled receptor signaling principles.

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