Biology:GPR139

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


G-protein coupled receptor 139 (GPR139) is a G protein-coupled receptor that in humans is encoded by the GPR139 gene.[1][2] It is coupled to the Gq/11 pathway, which is functionally opposite to the Gi/o inhibitory signaling of classical opioid receptors.[3] It is evolutionarily ancient and highly conserved across vertebrate phylogenetic taxa, suggesting a fundamental role in neurophysiology.[4][5] In humans, the receptor is exclusively expressed in the brain tissue, particularly in the medial habenula, septum, striatum, and hypothalamus.[1][4]

Historically classified as an orphan receptor, activated only by L-tryptophan and L-phenylalanine in very high concentrations,[6] GPR139 was deorphanized in 2025 as a novel, non-canonical opioid receptor specific to dynorphins, which selectively promote G protein activation of the receptor.[3] It is proposed to function as a molecular homeostatic brake for excessive canonical opioid and D2 receptor signaling.[3][4] Tryptamine is also a potent agonist of the GPR139 and has been reported to regulate sleep.[7]

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.[5][8]

Interactions with μ-opioid receptor

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

GPR139 constitutively promotes MOR desensitization.[9] 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.[9]

GPR139 counteracts MOR signaling at secondary effectors.[10] GPR139 expression inhibited GIRK channel activity through a Gq/11-dependent pathway. GPR139 activation increased cAMP production, also through a Gq/11-dependent pathway.[10]

Ligands

Agonists

Antagonists

References

  1. ↑ 1.0 1.1 "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. April 2003. doi:10.1073/pnas.0230374100. PMID 12679517. Bibcode: 2003PNAS..100.4903V. 
  2. ↑ "Entrez Gene: GPR139 G protein-coupled receptor 139". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=124274. 
  3. ↑ 3.0 3.1 3.2 "Homeostatic scaling of dynorphin signaling by a non-canonical opioid receptor". Nature Communications 16 (1). July 2025. doi:10.1038/s41467-025-62133-x. PMID 40701991. 
  4. ↑ 4.0 4.1 4.2 "GPR139, an Ancient Receptor and an Emerging Target for Neuropsychiatric and Behavioral Disorders". Molecular Neurobiology 62 (7): 9324-9337. March 2025. doi:10.1007/s12035-025-04828-2. PMID 40102345. 
  5. ↑ 5.0 5.1 "Pharmacology and function of the orphan GPR139 G protein-coupled receptor". Basic & Clinical Pharmacology & Toxicology 126 Suppl 6 (Suppl 6): 35–46. June 2020. doi:10.1111/bcpt.13263. PMID 31132229. 
  6. ↑ "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. November 2015. doi:10.1124/mol.115.100412. PMID 26349500. 
  7. ↑ 7.0 7.1 "Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis". Nat Neurosci. June 2026. doi:10.1038/s41593-026-02332-x. PMID 42321470. 
  8. ↑ "The role of orphan receptor GPR139 in neuropsychiatric behavior". Neuropsychopharmacology 47 (4): 902–913. March 2022. doi:10.1038/s41386-021-00962-2. PMID 33479510. 
  9. ↑ 9.0 9.1 "Genetic behavioral screen identifies an orphan anti-opioid system". Science 365 (6459): 1267–1273. September 2019. doi:10.1126/science.aau2078. PMID 31416932. 
  10. ↑ 10.0 10.1 "The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects" (in English). The Journal of Biological Chemistry 295 (31): 10822–10830. July 2020. doi:10.1074/jbc.AC120.014770. PMID 32576659. 
  11. ↑ "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. August 2021. doi:10.1021/acs.jmedchem.1c00820. PMID 34260228. 

Further reading

  • "Novel human G-protein-coupled receptors". Biochemical and Biophysical Research Communications 305 (1): 67–71. May 2003. doi:10.1016/S0006-291X(03)00709-5. PMID 12732197. 
  • "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. March 2002. doi:10.1006/geno.2002.6711. PMID 11863363. 
  • "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Letters 520 (1–3): 97–101. June 2002. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878. 
  • "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. April 2005. doi:10.1016/j.bbagen.2004.12.001. PMID 15777626. 
  • "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. May 2005. doi:10.1016/j.bbrc.2005.03.174. PMID 15845401. 



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