GPR139
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
G-protein coupled receptor 139 (GPR139) is a G protein-coupled receptor that in humans is encoded by the GPR139 gene.[5][6] It is coupled to the Gq/11 pathway, which is functionally opposite to the Gi/o inhibitory signaling of classical opioid receptors.[7] It is evolutionarily ancient and highly conserved across vertebrate phylogenetic taxa, suggesting a fundamental role in neurophysiology.[8][9] In humans, the receptor is exclusively expressed in the brain tissue, particularly in the medial habenula, septum, striatum, and hypothalamus.[5][8]
| GPR139 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | GPR139, GPRg1, PGR3, G protein-coupled receptor 139 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 618448; MGI: 2685341; HomoloGene: 45860; GeneCards: GPR139; OMA:GPR139 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Historically classified as an orphan receptor, activated only by L-tryptophan and L-phenylalanine in very high concentrations,[10] GPR139 was deorphanized in 2025 as a novel, non-canonical opioid receptor specific to dynorphins, which selectively promote G protein activation of the receptor.[7] It is proposed to function as a molecular homeostatic brake for excessive canonical opioid and D2 receptor signaling.[7][8]
Research has shown that mice with loss of GPR139 experience schizophrenia-like symptomatology that is rescued with the dopamine receptor antagonist haloperidol and the μ-opioid receptor antagonist naltrexone.[9][11]
Interactions with μ-opioid receptor
GPR139 appears to counter μ-opioid receptors (MOR) through multiple mechanisms.
GPR139 constitutively promotes MOR desensitization.[12] Expression of GPR139 at stoichiometric levels promoted β-arrestin recruitment to activated MORs. Appropriately, expression inhibited MOR — induced G protein activation. Overexpression of GPR139, but not stoichiometric expression, also decreased MOR at the cell surface.[12]
GPR139 counteracts MOR signaling at secondary effectors.[13] GPR139 expression inhibited GIRK channel activity through a Gq/11-dependent pathway. GPR139 activation increased cAMP production, also through a Gq/11-dependent pathway.[13]
Ligands
Agonists
- JNJ-63533054
- Zelatriazin (TAK-41), (NBI-1065846) a potent, and GPR139 receptor selective agonist [14] which was in clinical trials to gauge the efficacy for treating psychiatric conditions such as major depressive disorder and the negative symptoms of schizophrenia, but was later dropped from development.
- TC-O 9311 [444932-31-4]
