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GPR139

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From Wikipedia, the free encyclopedia

Protein-coding gene in the species Homo sapiens

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	20,028,239bp^[1]
Band	16p12.3	End	20,073,890bp^[1]

Gene location (Mouse)

Chr.	Chromosome 7 (mouse)^[2]

Band	7\|7 F2	Start	118,739,970bp^[2]
Band	7\|7 F2	End	118,783,826bp^[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 aG protein-coupled receptor that in humans is encoded by theGPR139gene.^[5]^[6] It is coupled to theG_q/11 pathway, which is functionally opposite to theG_i/o inhibitory signaling of classicalopioid receptors.^[7] It is evolutionarily ancient and highly conserved acrossvertebrate phylogenetic taxa, suggesting a fundamental role inneurophysiology.^[8]^[9] In humans, the receptor is exclusively expressed in thebrain tissue, particularly in themedial habenula, septum,striatum, andhypothalamus.^[5]^[8]

Historically classified as anorphan receptor, activated only byL-tryptophan andL-phenylalanine in very high concentrations,^[10] GPR139 was deorphanized in 2025 as a novel, non-canonicalopioid receptor specific todynorphins, which selectively promoteG protein activation of the receptor.^[7] It is proposed to function as a molecular homeostatic brake for excessive canonicalopioid andD2 receptor signaling.^[7]^[8]

Research has shown that mice with loss of GPR139 experienceschizophrenia-like symptomatology that is rescued with thedopamine receptor antagonist haloperidol and theμ-opioid receptor antagonist naltrexone.^[9]^[11]

Interactions with μ-opioid receptor

[edit]

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

GPR139 constitutively promotes MORdesensitization.^[12] Expression of GPR139 atstoichiometric levels promotedβ-arrestin recruitment to activated MORs. Appropriately, expression inhibited MOR — inducedG protein activation.Overexpression of GPR139, but not stoichiometric expression, also decreased MOR at thecell surface.^[12]

GPR139 counteracts MOR signaling at secondaryeffectors.^[13] GPR139 expression inhibitedGIRK channel activity through aGq/11-dependent pathway. GPR139 activation increasedcAMP production, also through a Gq/11-dependent pathway.^[13]

Ligands

[edit]

Agonists

[edit]

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 asmajor depressive disorder and the negative symptoms ofschizophrenia, but was later dropped from development.
TC-O 9311 [444932-31-4]

Antagonists

[edit]

JNJ-3792165

References

[edit]

^^a ^b ^cGRCh38: Ensembl release 89: ENSG00000180269 –Ensembl, May 2017
^^a ^b ^cGRCm38: Ensembl release 89: ENSMUSG00000066197 –Ensembl, May 2017
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^^a ^bVassilatis 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.
^"Entrez Gene: GPR139 G protein-coupled receptor 139".
^^a ^b ^cLi 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.
^^a ^b ^cChan 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.
^^a ^bVedel 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.
^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.
^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.
^^a ^bWang 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.
^^a ^bStoveken 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.
^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.

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.

Cell surface receptor:G protein-coupled receptors

Class A:Rhodopsin-like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3
Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)
Serotonin	(all but5-HT3)5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)
Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2),EP (1 2 3 4),FP Prostacyclin Thromboxane
Other	Bile acid Cannabinoid (CB1 CB2,GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Hydroxycarboxylic acids 1 2 3 Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide

B/W (1
2)
FF (1
2)
S
Y (1
2
4
5)
Neuromedin (B
U (1
2))
Neurotensin (1
2)

Other

Anaphylatoxin (C3a
C5a (1
2))
Angiotensin (1
2)
Apelin
Bombesin
- BRS3
- GRPR
- NMBR)
- Bradykinin (B1
- B2)
Chemerin
- 1
- 2
Chemokine
Cholecystokinin (A
B)
Endothelin
- A
- B
Formyl peptide (1
2
3)
FSH
Galanin (1
2
3)
Gonadotropin-releasing hormone (1
2)
Ghrelin
Kisspeptin
Luteinizing hormone/choriogonadotropin
MAS (1
1L
D
E
F
G
X1
X2
X3
X4)
Melanocortin (1
2
3
4
5)
MCHR (1
2)
Motilin
Opioid (Delta
Kappa
Mu
Nociceptin &Zeta, but notSigma)
Orexin (1
2)
Oxytocin
Prokineticin (1
2)
Prolactin-releasing peptide
Relaxin (1
2
3
4)
Somatostatin (1
2
3
4
5)
Tachykinin (1
2
3)
Thyrotropin
Thyrotropin-releasing hormone
Urotensin-II
Vasopressin (1A
1B
2)

Miscellaneous

Taste, bitter	TAS2R 1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor type 1
Orphan	GPR (3 4 6 12 15 17 18 19 20 21 22 26 27 31 32 33 34 35 37 39 42 45 50 52 55 61 62 63 65 68 75 78 82 83 84 85 87 88 101 103 109A 119 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)
Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B:Secretin-like

Adhesion	ADGRB Brain-specific angiogenesis inhibitor 1 2 3 ADGRC Cadherin 1 2 3 ADGRE EMR 1 2 3 CD97 ADGRG 1 2 3 4 5 6 7 ADGRL Latrophilin 1 2 3 ELTD1
Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)
Other	Calcitonin CALCRL Corticotropin-releasing hormone (1 2) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C:Metabotropic glutamate /pheromone

Taste, sweet	TAS1R 1 2 3 Vomeronasal receptor, type 2
Other	Calcium-sensing receptor GABA_B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)