GPR139

GPR139
Identifiers
Aliases	GPR139 , GPRg1, PGR3, G protein-coupled receptor 139
External IDs	OMIM: 618448; MGI: 2685341; HomoloGene: 45860; GeneCards: GPR139; OMA:GPR139 - orthologs
Gene location (Human) Chr. Chromosome 16 (human) [1] Band 16p12.3 Start 20,028,239 bp [1] End 20,073,890 bp [1]
Gene location (Mouse) Chr. Chromosome 7 (mouse) [2] Band 7|7 F2 Start 118,739,970 bp [2] End 118,783,826 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle caudate nucleus putamen nucleus accumbens hypothalamus bone marrow substantia nigra pituitary gland C1 segment muscle tissue Top expressed in lumbar spinal ganglion habenula medial vestibular nucleus deep cerebellar nuclei mammillary body dorsal tegmental nucleus dorsomedial hypothalamic nucleus lateral hypothalamus central gray substance of midbrain embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity protein dimerization activity signal transducer activity neuropeptide receptor activity Cellular component integral component of membrane plasma membrane membrane Biological process G protein-coupled receptor signaling pathway phospholipase C-activating G protein-coupled receptor signaling pathway neuropeptide signaling pathway signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 124274 209776 Ensembl ENSG00000180269 ENSMUSG00000066197 UniProt Q6DWJ6 Q80UC8 RefSeq (mRNA) NM_001002911 NM_001318483 NM_001024138 RefSeq (protein) NP_001002911 NP_001305412 NP_001019309 Location (UCSC) Chr 16: 20.03 – 20.07 Mb Chr 7: 118.74 – 118.78 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 G_q/11 pathway, which is functionally opposite to the G_i/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]}

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]

Antagonists

• JNJ-3792165

References

1. GRCh38: Ensembl release 89: ENSG00000180269 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000066197 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, et al. (April 2003). "The G protein-coupled receptor repertoires of human and mouse". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4903–4908. Bibcode:2003PNAS..100.4903V. doi: 10.1073/pnas.0230374100 . PMC   153653 . PMID   12679517.
6. "Entrez Gene: GPR139 G protein-coupled receptor 139".
7. Li X, Winters ND, Pandey S, Lankford C, Stoveken HM, Smith E, et al. (July 2025). "Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor". Nature Communications. 16 (1) 6786. doi: 10.1038/s41467-025-62133-x . PMC   12287315 . PMID   40701991.
8. Chan M, Ogawa S (March 2025). "GPR139, an Ancient Receptor and an Emerging Target for Neuropsychiatric and Behavioral Disorders". Molecular Neurobiology. 62 (7): 9324–9337. doi:10.1007/s12035-025-04828-2. ISSN   0893-7648. PMC   12208981 . PMID   40102345.
9. Vedel L, Nøhr AC, Gloriam DE, Bräuner-Osborne H (June 2020). "Pharmacology and function of the orphan GPR139 G protein-coupled receptor". Basic & Clinical Pharmacology & Toxicology. 126 Suppl 6 (Suppl 6): 35–46. doi:10.1111/bcpt.13263. PMC   7318219 . PMID   31132229.
10. Liu C, Bonaventure P, Lee G, Nepomuceno D, Kuei C, Wu J, et al. (November 2015). "GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine". Molecular Pharmacology. 88 (5): 911–925. doi:10.1124/mol.115.100412. PMID   26349500.
11. Dao M, Stoveken HM, Cao Y, Martemyanov KA (March 2022). "The role of orphan receptor GPR139 in neuropsychiatric behavior". Neuropsychopharmacology. 47 (4): 902–913. doi:10.1038/s41386-021-00962-2. PMC   8882194 . PMID   33479510. S2CID   231668867.
12. Wang D, Stoveken HM, Zucca S, Dao M, Orlandi C, Song C, et al. (September 2019). "Genetic behavioral screen identifies an orphan anti-opioid system". Science. 365 (6459): 1267–1273. doi:10.1126/science.aau2078. PMC   7074901 . PMID   31416932.
13. Stoveken HM, Zucca S, Masuho I, Grill B, Martemyanov KA (July 2020). "The orphan receptor GPR139 signals via G_q/11 to oppose opioid effects". The Journal of Biological Chemistry. 295 (31): 10822–10830. doi: 10.1074/jbc.AC120.014770 . PMC   7397111 . PMID   32576659.
14. Reichard HA, Schiffer HH, Monenschein H, Atienza JM, Corbett G, Skaggs AW, et al. (August 2021). "Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia". Journal of Medicinal Chemistry. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID   34260228. S2CID   235908256.

Further reading

• Vanti WB, Nguyen T, Cheng R, Lynch KR, George SR, O'Dowd BF (May 2003). "Novel human G-protein-coupled receptors". Biochemical and Biophysical Research Communications. 305 (1): 67–71. doi:10.1016/S0006-291X(03)00709-5. PMID   12732197.
• Ottolenghi C, Fellous M, Barbieri M, McElreavey K (March 2002). "Novel paralogy relations among human chromosomes support a link between the phylogeny of doublesex-related genes and the evolution of sex determination". Genomics. 79 (3): 333–343. doi:10.1006/geno.2002.6711. PMID   11863363.
• Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S (June 2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Letters. 520 (1–3): 97–101. doi:10.1016/S0014-5793(02)02775-8. PMID   12044878. S2CID   7116392.
• Gloriam DE, Schiöth HB, Fredriksson R (April 2005). "Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship". Biochimica et Biophysica Acta (BBA) - General Subjects. 1722 (3): 235–246. doi:10.1016/j.bbagen.2004.12.001. PMID   15777626.
• Matsuo A, Matsumoto S, Nagano M, Masumoto KH, Takasaki J, Matsumoto M, et al. (May 2005). "Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system". Biochemical and Biophysical Research Communications. 331 (1): 363–369. doi:10.1016/j.bbrc.2005.03.174. PMID   15845401.