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GPR84

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 120

Nomenclature: GPR84

Family: Class A Orphans

This receptor has a proposed ligand; see the Latest Pairings page for more information.

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 7 396 12q13.13 GPR84 G protein-coupled receptor 84 17
Mouse 7 396 15 F3 Gpr84 G protein-coupled receptor 84
Rat 7 396 7q36 Gpr84 G protein-coupled receptor 84
Previous and Unofficial Names Click here for help
GPCR4 | Inflammation-related G-protein coupled receptor EX33
Database Links Click here for help
Specialist databases
GPCRdb gpr84_human (Hs), gpr84_mouse (Mm)
Other databases
Alphafold Q9NQS5 (Hs), Q8CIM5 (Mm)
ChEMBL Target CHEMBL3714079 (Hs), CHEMBL4523386 (Mm)
Ensembl Gene ENSG00000139572 (Hs), ENSMUSG00000063234 (Mm), ENSRNOG00000036834 (Rn)
Entrez Gene 53831 (Hs), 80910 (Mm), 688730 (Rn)
Human Protein Atlas ENSG00000139572 (Hs)
KEGG Gene hsa:53831 (Hs), mmu:80910 (Mm), rno:688730 (Rn)
OMIM 606383 (Hs)
Pharos Q9NQS5 (Hs)
RefSeq Nucleotide NM_020370 (Hs), NM_030720 (Mm), NM_001109509 (Rn)
RefSeq Protein NP_065103 (Hs), NP_109645 (Mm), NP_001102979 (Rn)
UniProtKB Q9NQS5 (Hs), Q8CIM5 (Mm)
Wikipedia GPR84 (Hs)
Natural/Endogenous Ligands Click here for help
Medium-chain-length fatty acids
Comments: Medium chain free fatty acids with carbon chain lengths of 9-14 have been shown by several groups to activate GPR84 [11-12,14]. A surrogate ligand for GPR84, 6-n-octylaminouracil, has also been proposed [12].

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
OX04529 Small molecule or natural product Hs Biased agonist 10.7 pEC50 15
⤷ pEC50 10.7 (EC50 1.8x10-11 M) [15]
Description: Measured as inhibition of forskolin-induced cAMP production in CHO-hGPR84 cells
PSB-17365 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Agonist 8.7 pEC50 9
⤷ pEC50 8.7 (EC50 2x10-9 M) [9]
PSB-1584 Small molecule or natural product Hs Agonist 8.3 – 8.5 pEC50 9
⤷ pEC50 8.5 (EC50 3.2x10-9 M) [9]
Description: Potency in a β-arrestin recruitment assay.
pEC50 8.3 (EC50 5x10-9 M) [9]
Description: Potency in a cAMP assay.
DL-175 Small molecule or natural product Hs Agonist 7.9 pEC50 7,15
⤷ pEC50 7.9 (EC50 1.24x10-8 M) orthosteric [7,15]
Description: Measured as inhibition of forskolin-induced cAMP production in CHO-hGPR84 cells
6-n-octylaminouracil Small molecule or natural product Immunopharmacology Ligand Hs Full agonist 7.0 pEC50 12
⤷ pEC50 7.0 (EC50 1.05x10-7 M) [12]
decanoic acid Small molecule or natural product Ligand has a PDB structure Hs Full agonist 5.0 – 5.4 pEC50 11,14
⤷ pEC50 5.0 – 5.4 [11,14]
undecanoic acid Small molecule or natural product Ligand has a PDB structure Hs Agonist 5.1 pEC50 14
⤷ pEC50 5.1 (EC50 8x10-6 M) [14]
lauric acid Small molecule or natural product Ligand has a PDB structure Hs Agonist 5.1 pEC50 14
⤷ pEC50 5.1 (EC50 9x10-6 M) [14]
2-hydroxylauric acid Small molecule or natural product Hs Full agonist 5.0 pEC50 12
⤷ pEC50 5.0 (EC50 9.9x10-6 M) [12]
3-hydroxylauric acid Small molecule or natural product Hs Full agonist 4.9 pEC50 12
⤷ pEC50 4.9 (EC50 1.3x10-5 M) [12]
2-hydroxy capric acid Small molecule or natural product Hs Full agonist 4.5 pEC50 12
⤷ pEC50 4.5 (EC50 3.1x10-5 M) [12]
3-hydroxy capric acid Small molecule or natural product Hs Full agonist 3.6 pEC50 12
⤷ pEC50 3.6 (EC50 2.3x10-4 M) [12]
Embelin Small molecule or natural product Ligand has a PDB structure Hs Agonist - - 7
⤷ orthosteric [7]
PSB-16434 Small molecule or natural product Hs Agonist - - 7
⤷ orthosteric [7]
ZQ-16 Small molecule or natural product Hs Agonist - - 7
⤷ orthosteric [7]
6-nonylpyridine-2,4-diol Small molecule or natural product Ligand has a PDB structure Hs Agonist - - 7
⤷ orthosteric [7]
Agonist Comments
Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [12,14]. A surrogate ligand for GPR84, 6-n-octylaminouracil, has also been proposed [12].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GLPG1205 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 7.0 – 11.0 pIC50 5
⤷ pIC50 7.0 – 11.0 (IC50 1x10-7 – 1x10-11 M) [5]
Description: Binned data from [35S] GTPγS binding experiments using menbranes from cell that stably express GPR84.
PBI-4547 Small molecule or natural product Hs Antagonist 4.8 pIC50 10
⤷ pIC50 4.8 (IC50 1.7x10-5 M) [10]
Description: Antagonisn of sodium decanoate-mediated GPR84 activation, determined in a BRET biosensor assay measuring Gαi protein activation in HEK293 cells.
setogepram Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 3.4 pIC50 2
⤷ pIC50 3.4 (IC50 3.981x10-4 M) [2]
Description: Measuring antagonist-dependent inhibition of Gαiactivation by sodium decanoate (agonist) in receptor transfected HEK293 cells.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
DIM Small molecule or natural product Hs Agonist - - 7
⤷ [7]
Immunopharmacology Comments
GPR84 is proposed as a receptor for free fatty acids. It is predominantly expressed in immune system-related tissues and cells [4] and appears to play an important role in inflammation, immunity, and cancer. Its expression is upregulated under inflammatory conditions (e.g. in LPS-exposed macrophages). GPR84 regulates the production of the pro-inflammatory cytokine IL-12, and thus is involved in the balance of T helper cell responses, and pathological processes in inflammatory diseases [13]. This receptor may provide a direct link between fatty acid metabolism and immune responses [3]. GPR84 agonists are proposed as novel immune response activators as immuno-oncology agents, or could have anti-inflammatory effects mediated via agonist-induced receptor desensitization (functional blockade). Studies in Gpr84 knockout mice indicate that it plays a deleterious role in fibrotic kidney disease models [2].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
References:  14
Tissue Distribution Click here for help
Bone marrow, lung, peripheral blood leukocytes
Species:  Human
Technique:  Northern blot
References:  17
Neutrophils, eosinophils
Species:  Human
Technique:  RT-PCR
References:  17
Brain (medulla, substantia nigra, thalamus, corpus callosum), spinal cord, heart, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, leukocytes
Species:  Human
Technique:  Northern blot
References:  16
Spleen, liver
Species:  Mouse
Technique:  Northern blot
References:  16
Bone marrow, spleen, lung, testis, peritoneal macrophages
Species:  Mouse
Technique:  RT-PCR
References:  13-14
Primary non-inflammatory macrophages
Species:  Mouse
Technique:  Microarray analysis
References:  6
Expression Datasets Click here for help

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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]

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Physiological Functions Click here for help
Medium chain free fatty acids amplify lipopolysaccharide-stimulated production of IL-12 p40 through GPR84
Species:  Human
Tissue:  Leukocytes
References:  4,13
Physiological Consequences of Altering Gene Expression Click here for help
Primary stimulation of T cells with anti-CD3 resulted in increased IL-4 production in GPR84 knockout mice. Th2 effector cells from knockout mice produce higher levels of IL-4, IL-5 and IL-13
Species:  Mouse
Tissue:  T cells
Technique:  Gene knockouts
References:  13
Gene Expression and Pathophysiology Comments
In mice suffering from endotoxemia and experimental autoimmune encephalomyelitis (model of multiple sclerosis), microglia express GPR84 in a strong and sustained manner, induced by TNF [1].
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  G37D
Global MAF (%):  1
Subpopulation MAF (%):  ASN: 4
Minor allele count:  T=0.011/25
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  VAR_049397, rs11170883
Validation:  1000 Genomes, HapMap
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  W370H
Global MAF (%):  1
Subpopulation MAF (%):  ASN: 4
Minor allele count:  G=0.011/23
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  rs77759698
Validation:  1000 Genomes, Frequency
General Comments
GPR84 expression is induced in macrophages and microglia by LPS [1,14]. The receptor is important for eye development in Xenopus laevis [8].

References

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1. Bouchard C, Pagé J, Bédard A, Tremblay P, Vallières L. (2007) G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions. Glia, 55 (8): 790-800. [PMID:17390309]

2. Gagnon L, Leduc M, Thibodeau JF, Zhang MZ, Grouix B, Sarra-Bournet F, Gagnon W, Hince K, Tremblay M, Geerts L et al.. (2018) A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84. Am J Pathol, 188 (5): 1132-1148. [PMID:29454750]

3. Huang Q, Feng D, Liu K, Wang P, Xiao H, Wang Y, Zhang S, Liu Z. (2014) A medium-chain fatty acid receptor Gpr84 in zebrafish: expression pattern and roles in immune regulation. Dev Comp Immunol, 45 (2): 252-8. [PMID:24704214]

4. Ichimura A, Hirasawa A, Hara T, Tsujimoto G. (2009) Free fatty acid receptors act as nutrient sensors to regulate energy homeostasis. Prostaglandins Other Lipid Mediat, 89 (3-4): 82-8. [PMID:19460454]

5. Labeguere FG, Nwesome GJR, Alvey LJ, Saniere LRM, Fletcher SR. (2013) Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders. Patent number: WO2013092791A1. Assignee: Galapagos Nv. Priority date: 22/12/2011. Publication date: 27/06/2013.

6. Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ. (2008) Expression analysis of G Protein-Coupled Receptors in mouse macrophages. Immunome Res, 4: 5. [PMID:18442421]

7. Marsango S, Barki N, Jenkins L, Tobin AB, Milligan G. (2022) Therapeutic validation of an orphan G protein-coupled receptor: The case of GPR84. Br J Pharmacol, 179 (14): 3529-3541. [PMID:32869860]

8. Perry KJ, Johnson VR, Malloch EL, Fukui L, Wever J, Thomas AG, Hamilton PW, Henry JJ. (2010) The G-protein-coupled receptor, GPR84, is important for eye development in Xenopus laevis. Dev Dyn, 239 (11): 3024-37. [PMID:20925114]

9. Pillaiyar T, Köse M, Namasivayam V, Sylvester K, Borges G, Thimm D, von Kügelgen I, Müller CE. (2018) 6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84). ACS Omega, 3 (3): 3365-3383. [PMID:30023867]

10. Simard JC, Thibodeau JF, Leduc M, Tremblay M, Laverdure A, Sarra-Bournet F, Gagnon W, Ouboudinar J, Gervais L, Felton A et al.. (2020) Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease. Sci Rep, 10 (1): 12778. [PMID:32728158]

11. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

12. Suzuki M, Takaishi S, Nagasaki M, Onozawa Y, Iino I, Maeda H, Komai T, Oda T. (2013) Medium-chain Fatty Acid-sensing Receptor, GPR84, Is a Proinflammatory Receptor. J Biol Chem, 288 (15): 10684-91. [PMID:23449982]

13. Venkataraman C, Kuo F. (2005) The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol Lett, 101 (2): 144-53. [PMID:15993493]

14. Wang J, Wu X, Simonavicius N, Tian H, Ling L. (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem, 281 (45): 34457-64. [PMID:16966319]

15. Wang P, Raja A, Luscombe VB, Bataille CJR, Lucy D, Rogga VV, Greaves DR, Russell AJ. (2024) Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists. J Med Chem, 67 (1): 110-137. [PMID:38146625]

16. Wittenberger T, Schaller HC, Hellebrand S. (2001) An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J Mol Biol, 307 (3): 799-813. [PMID:11273702]

17. Yousefi S, Cooper PR, Potter SL, Mueck B, Jarai G. (2001) Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes. J Leukoc Biol, 69 (6): 1045-52. [PMID:11404393]

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