<i>GPR84</i> | Class A Orphans | IUPHAR/BPS Guide to PHARMACOLOGY

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GPR84

target has curated data in GtoImmuPdb

Target id: 120

Nomenclature: GPR84

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

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

Gene and Protein Information
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 14
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
GPCR4 | Inflammation-related G-protein coupled receptor EX33
Database Links
Specialist databases
GPCRDB gpr84_human (Hs), gpr84_mouse (Mm)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
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 [9-10,12]. A surrogate ligand for GPR84, 6-n-octylaminouracil, has also been proposed [10].

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PSB-17365 Hs Agonist 8.7 pEC50 8
pEC50 8.7 (EC50 2x10-9 M) [8]
6-n-octylaminouracil Hs Full agonist 7.0 pEC50 10
pEC50 7.0 (EC50 1.05x10-7 M) [10]
decanoic acid Hs Full agonist 5.0 – 5.4 pEC50 9,12
pEC50 5.0 – 5.4 [9,12]
undecanoic acid Hs Agonist 5.1 pEC50 12
pEC50 5.1 (EC50 8x10-6 M) [12]
lauric acid Hs Agonist 5.1 pEC50 12
pEC50 5.1 (EC50 9x10-6 M) [12]
2-hydroxylauric acid Hs Full agonist 5.0 pEC50 10
pEC50 5.0 (EC50 9.9x10-6 M) [10]
3-hydroxylauric acid Hs Full agonist 4.9 pEC50 10
pEC50 4.9 (EC50 1.3x10-5 M) [10]
2-hydroxy capric acid Hs Full agonist 4.5 pEC50 10
pEC50 4.5 (EC50 3.1x10-5 M) [10]
3-hydroxy capric acid Hs Full agonist 3.6 pEC50 10
pEC50 3.6 (EC50 2.3x10-4 M) [10]
Agonist Comments
Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [10,12]. A surrogate ligand for GPR84, 6-n-octylaminouracil, has also been proposed [10].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GLPG1205 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.
setogepram 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.
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. GPR84 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 [11]. GPR84 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-inflammaotry 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
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
References:  12
Tissue Distribution
Bone marrow, lung, peripheral blood leukocytes
Species:  Human
Technique:  Northern blot
References:  14
Neutrophils, eosinophils
Species:  Human
Technique:  RT-PCR
References:  14
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:  13
Spleen, liver
Species:  Mouse
Technique:  Northern blot
References:  13
Bone marrow, spleen, lung, testis, peritoneal macrophages
Species:  Mouse
Technique:  RT-PCR
References:  11-12
Primary non-inflammatory macrophages
Species:  Mouse
Technique:  Microarray analysis
References:  6
Expression Datasets

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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
Medium chain free fatty acids amplify lipopolysaccharide-stimulated production of IL-12 p40 through GPR84
Species:  Human
Tissue:  Leukocytes
References:  4,11
Physiological Consequences of Altering Gene Expression
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:  11
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
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: 
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: 
Validation:  1000 Genomes, Frequency
General Comments
GPR84 expression is induced in macrophages and microglia by LPS [1,12]. The receptor is important for eye development in Xenopus laevis [7].

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. 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]

8. Pillaiyar T, Köse M, Namasivayam V, Sylvester K, Borges G, Thimm D, Von Kügelen 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.

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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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