Top ▲

GPR139

Click here for help

Target id: 130

Nomenclature: GPR139

Family: Class A Orphans

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 353 16p12.3 GPR139 G protein-coupled receptor 139 1,5,9
Mouse 7 345 7 F2 Gpr139 G protein-coupled receptor 139 5,9
Rat 7 345 1q35 Gpr139 G protein-coupled receptor 139 1,5
Previous and Unofficial Names Click here for help
G(q)-coupled orphan receptor GPRg1 | GPRG1 | G-protein-coupled receptor PGR3
Database Links Click here for help
Specialist databases
GPCRdb gp139_human (Hs), gp139_mouse (Mm), gp139_rat (Rn)
Other databases
Alphafold Q6DWJ6 (Hs), Q80UC8 (Mm), P0C0W8 (Rn)
ChEMBL Target CHEMBL3632455 (Hs), CHEMBL4888453 (Rn)
Ensembl Gene ENSG00000180269 (Hs), ENSMUSG00000066197 (Mm), ENSRNOG00000023863 (Rn)
Entrez Gene 124274 (Hs), 209776 (Mm), 293545 (Rn)
Human Protein Atlas ENSG00000180269 (Hs)
KEGG Gene hsa:124274 (Hs), mmu:209776 (Mm), rno:293545 (Rn)
Pharos Q6DWJ6 (Hs)
RefSeq Nucleotide NM_001002911 (Hs), NM_001024138 (Mm), NM_00102424 (Rn)
RefSeq Protein NP_001002911 (Hs), NP_001019309 (Mm), NP_001019412 (Rn)
UniProtKB Q6DWJ6 (Hs), Q80UC8 (Mm), P0C0W8 (Rn)
Wikipedia GPR139 (Hs)
Natural/Endogenous Ligands Click here for help
L-phenylalanine
L-tryptophan

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
JNJ-63533054 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Agonist 7.6 pKi 4
⤷ pKi 7.6 (Ki 2.4x10-8 M) [4]
zelatriazin (TAK-041) Small molecule or natural product Hs Agonist 6.9 pKi 7
⤷ pKi 6.9 (Ki 1.19x10-7 M) [7]
Description: Radioligand competition binding assay using membranes isolated from CHO-T-REx cells that stably express the hGPR139
L-tryptophan Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.1 pKi 4
⤷ pKi 3.1 (Ki 7.38x10-4 M) [4]
Description: Inhibition equilibrium constant from a radioligand membrane binding assay.
L-phenylalanine Small molecule or natural product Primary target of this compound Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.1 pKi 4
⤷ pKi 3.1 (Ki 8.72x10-4 M) [4]
Description: Inhibition equilibrium constant from a radioligand membrane binding assay.
zelatriazin (TAK-041) Small molecule or natural product Hs Agonist 7.7 pEC50 7
⤷ pEC50 7.7 (EC50 2.2x10-8 M) [7]
Description: Agonist-induced in vitro calcium mobilization assay, using CHO-T-REx cells stably expressing hGPR139
compound 1a [PMID: 24900311] Small molecule or natural product Hs Full agonist 7.4 pEC50 8
⤷ pEC50 7.4 (EC50 3.9x10-8 M) [8]
L-tryptophan Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.7 pEC50 3
⤷ pEC50 3.7 (EC50 2.2x10-4 M) [3]
L-phenylalanine Small molecule or natural product Primary target of this compound Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.5 pEC50 3
⤷ pEC50 3.5 (EC50 3.2x10-4 M) [3]
L-tryptophan Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.6 pIC50 4
⤷ pIC50 4.6 (IC50 2.6x10-5 M) [4]
Description: Measured using a GTPγS assay in transfected COS7 cells.
L-phenylalanine Small molecule or natural product Primary target of this compound Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.5 pIC50 4
⤷ pIC50 4.5 (IC50 3.1x10-5 M) [4]
Description: Measured using a GTPγS assay in transfected COS7 cells.
LP-360924 Small molecule or natural product Hs Agonist - - 2
⤷ [2]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
NCRW0005-F05 Small molecule or natural product Hs Antagonist 6.7 pIC50 11
⤷ pIC50 6.7 (IC50 2.1x10-7 M) [11]
NCRW0105-E06 Small molecule or natural product Hs Antagonist 6.3 pIC50 6
⤷ pIC50 6.3 (IC50 5.12x10-7 M) [6]
Description: Inhibition of Ca2+ mobilization
LP-471756 Small molecule or natural product Hs Antagonist 6.2 pIC50 2
⤷ pIC50 6.2 (IC50 6.4x10-7 M) [2]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Other - See Comments
Comments:  GPR139 is coupled with Gq/11 protein which leads to activation of serum response element (SRE) and cAMP response element (CRE) [5]. However, Susens et al. show that GPR139 signaling does not require Gi and Gq coupling [9]. Instead, it is mediated by an inhibitory G-protein and phospholipase C. Dimer formation may be required for proper signaling function.
References:  5
Tissue Distribution Click here for help
Central nervous system, mainly in the caudate putamen and hypothalamus
Species:  Human
Technique:  RT-PCR
References:  5
Various brain regions. High expression in putamen, medulla and caudate nucleus. Low expression in thalamus, amygdala and spinal cord.
Species:  Human
Technique:  Northern blot
References:  9
High expression in ventrolateral region of caudate putamen, habenular nucleus, zona incerta and medial mammillary nucleus.
Species:  Mouse
Technique:  in situ hybridisation
References:  5
Median habenular nucleus
Species:  Mouse
Technique:  in situ hybridisation
References:  9
Expression Datasets Click here for help

Show »

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Physiological Functions Comments
A forward genetic screen in a behavioural model using C. elegans suggests that GPR139 negatively regulates μ opioid receptor signalling [10].

References

Show »

1. Gloriam DE, Schiöth HB, Fredriksson R. (2005) Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship. Biochim Biophys Acta, 1722 (3): 235-46. [PMID:15777626]

2. Hu LA, Tang PM, Eslahi NK, Zhou T, Barbosa J, Liu Q. (2009) Identification of surrogate agonists and antagonists for orphan G-protein-coupled receptor GPR139. J Biomol Screen, 14 (7): 789-97. [PMID:19525486]

3. Isberg V, Andersen KB, Bisig C, Dietz GP, Bräuner-Osborne H, Gloriam DE. (2014) Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J Chem Inf Model, 54 (6): 1553-7. [PMID:24826842]

4. Liu C, Bonaventure P, Lee G, Nepomuceno D, Kuei C, Wu J, Li Q, Joseph V, Sutton SW, Eckert W et al.. (2015) GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol Pharmacol, 88 (5): 911-25. [PMID:26349500]

5. Matsuo A, Matsumoto S, Nagano M, Masumoto KH, Takasaki J, Matsumoto M, Kobori M, Katoh M, Shigeyoshi Y. (2005) Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system. Biochem Biophys Res Commun, 331 (1): 363-9. [PMID:15845401]

6. Pallareti L, Rath TF, Trapkov B, Tsonkov T, Nielsen AT, Harpsøe K, Gentry PR, Bräuner-Osborne H, Gloriam DE, Foster SR. (2023) Pharmacological characterization of novel small molecule agonists and antagonists for the orphan receptor GPR139. Eur J Pharmacol, 943: 175553. [PMID:36736525]

7. Reichard HA, Schiffer HH, Monenschein H, Atienza JM, Corbett G, Skaggs AW, Collia DR, Ray WJ, Serrats J, Bliesath J et al.. (2021) Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia. J Med Chem, 64 (15): 11527-11542. [PMID:34260228]

8. Shi F, Shen JK, Chen D, Fog K, Thirstrup K, Hentzer M, Karlsson JJ, Menon V, Jones KA, Smith KE et al.. (2011) Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139. ACS Med Chem Lett, 2 (4): 303-6. [PMID:24900311]

9. Süsens U, Hermans-Borgmeyer I, Urny J, Schaller HC. (2006) Characterisation and differential expression of two very closely related G-protein-coupled receptors, GPR139 and GPR142, in mouse tissue and during mouse development. Neuropharmacology, 50 (4): 512-20. [PMID:16378626]

10. Wang D, Stoveken HM, Zucca S, Dao M, Orlandi C, Song C, Masuho I, Johnston C, Opperman KJ, Giles AC et al.. (2019) Genetic behavioral screen identifies an orphan anti-opioid system. Science, 365 (6459): 1267-1273. [PMID:31416932]

11. Wang J, Zhu LY, Liu Q, Hentzer M, Smith GP, Wang MW. (2015) High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139. Acta Pharmacol Sin, 36 (7): 874-8. [PMID:26027661]

Contributors

Show »

How to cite this page