GPR139

GPR139
Identifiers
AliasesGPR139, GPRg1, PGR3, G protein-coupled receptor 139
External IDsOMIM: 618448; MGI: 2685341; GeneCards: GPR139
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
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 MbChr 7: 118.74 – 118.78 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

G-protein coupled receptor 139 (GPR139) is a G protein-coupled receptor that in humans is encoded by the GPR139 gene. It is coupled to the Gq/11 pathway, which is functionally opposite to the Gi/o inhibitory signaling of classical opioid receptors. It is evolutionarily ancient and highly conserved across vertebrate phylogenetic taxa, suggesting a fundamental role in neurophysiology. In humans, the receptor is exclusively expressed in the brain tissue, particularly in the medial habenula, septum, striatum, and hypothalamus.

Historically classified as an orphan receptor, activated only by L-tryptophan and L-phenylalanine in very high concentrations, GPR139 was deorphanized in 2025 as a novel, non-canonical opioid receptor specific to dynorphins, which selectively promote G protein activation of the receptor. It is proposed to function as a molecular homeostatic brake for excessive canonical opioid and D2 receptor signaling. Tryptamine is also a potent agonist of the GPR139 and has been reported to regulate sleep.

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.

Interactions with μ-opioid receptor

GPR139 appears to counter μ-opioid receptors (MOR) through multiple mechanisms.

GPR139 constitutively promotes MOR desensitization. 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.

GPR139 counteracts MOR signaling at secondary effectors. GPR139 expression inhibited GIRK channel activity through a Gq/11-dependent pathway. GPR139 activation increased cAMP production, also through a Gq/11-dependent pathway.

Ligands

Agonists

Antagonists

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000180269 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 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". Archived from the original on 2025-04-24.
  7. 1 2 3 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. 1 2 3 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. PMC 12208981. PMID 40102345.
  9. 1 2 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. 1 2 Cao H, Wang K, Zhao J, Zha ZH, Zhang Q, Xiu Y, et al. (June 2026). "Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis". Nat Neurosci. doi:10.1038/s41593-026-02332-x. PMID 42321470.
  12. ↑ 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.
  13. 1 2 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.
  14. 1 2 Stoveken HM, Zucca S, Masuho I, Grill B, Martemyanov KA (July 2020). "The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects". The Journal of Biological Chemistry. 295 (31): 10822–10830. doi:10.1074/jbc.AC120.014770. PMC 7397111. PMID 32576659.
  15. ↑ 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.