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GPR18

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Target not currently curated in GtoImmuPdb

Target id: 89

Nomenclature: GPR18

Family: GPR18, GPR55 and GPR119

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 7 331 13q32.3 GPR18 G protein-coupled receptor 18 6
Mouse 7 331 14 65.86 cM Gpr18 G protein-coupled receptor 18
Rat 7 331 15q25 Gpr18 G protein-coupled receptor 18
Previous and Unofficial Names Click here for help
GPCRW | NAGly receptor | N-arachidonoyol glycine receptor
Database Links Click here for help
Specialist databases
GPCRdb gpr18_human (Hs), gpr18_mouse (Mm), gpr18_rat (Rn)
Other databases
Alphafold Q14330 (Hs), Q8K1Z6 (Mm), A1A5S3 (Rn)
ChEMBL Target CHEMBL2384898 (Hs)
Ensembl Gene ENSG00000125245 (Hs), ENSMUSG00000050350 (Mm), ENSRNOG00000012628 (Rn)
Entrez Gene 2841 (Hs), 110168 (Mm), 679957 (Rn)
Human Protein Atlas ENSG00000125245 (Hs)
KEGG Gene hsa:2841 (Hs), mmu:110168 (Mm), rno:679957 (Rn)
OMIM 602042 (Hs)
Pharos Q14330 (Hs)
RefSeq Nucleotide NM_005292 (Hs), NM_182806 (Mm), NM_001079710 (Rn)
RefSeq Protein NP_005283 (Hs), NP_877958 (Mm), NP_001073178 (Rn)
UniProtKB Q14330 (Hs), Q8K1Z6 (Mm), A1A5S3 (Rn)
Wikipedia GPR18 (Hs)
Natural/Endogenous Ligands Click here for help
N-arachidonoylglycine

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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
PSB-KK1415 Small molecule or natural product Hs Agonist 7.7 pEC50 9
⤷ pEC50 7.7 (EC50 1.91x10-8 M) [9]
N-arachidonoylglycine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.3 – 7.7 pEC50 12
⤷ pEC50 7.3 – 7.7 (EC50 4.45x10-8 – 2x10-8 M) [12]
PSB-KK1445 Small molecule or natural product Hs Agonist 7.3 pEC50 9
⤷ pEC50 7.3 (EC50 4.54x10-8 M) [9]
O-1602 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 7.2 pEC50 12
⤷ pEC50 7.2 (EC50 6.53x10-8 M) [12]
PSB-KD107 Small molecule or natural product Immunopharmacology Ligand Hs Agonist 6.3 pEC50 14
⤷ pEC50 6.3 (EC50 5.62x10-7 M) [14]
abnormal cannabidiol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 6.1 pEC50 12
⤷ pEC50 6.1 (EC50 8.357x10-7 M) [12]
Δ9-tetrahydrocannabinol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 6.0 pEC50 1,12
⤷ pEC50 6.0 (EC50 9.6x10-7 M) [1,12]
anandamide Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 5.4 pEC50 12
⤷ pEC50 5.4 (EC50 3.83x10-6 M) [12]
arachidonylcyclopropylamide Small molecule or natural product Hs Agonist 4.9 pEC50 12
⤷ pEC50 4.9 (EC50 1.35x10-5 M) [12]
cannabidiol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 4.3 pEC50 12
⤷ pEC50 4.3 (EC50 5.11x10-5 M) [12]
AM251 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 4.0 pEC50 12
⤷ pEC50 4.0 (EC50 9.64x10-5 M) [12]
Agonist Comments
Kohno et al. [8] screened a lipid library and identified an endogenous ligand, N-arachidonoylglycine (NAGly) by measuring an increase in intracellular Ca2+ concentrations in GPR18-transfected cells. NAGly also inhibited forskolin-induced cAMP production in a pertussis toxin–sensitive manner in the GPR18-transfected CHO cells, with an EC50 value of 20 nM. NAGly has been suggested to be an endogenous metabolite of the endocannabinoid anandamide, differing only in a change in the oxidation state of the carbon β to the amido nitrogen that greatly reduces agonist activity at cannabinoid receptors CB1 and CB2. McHugh et al. [11-12] reproduced the effect of NAGly in activating p44/42 MAPK in GPR18-transfected HEK293 cells, also showing that anandamide, Δ9-tetrahydrocannabinol and abnormal cannabidiol were agonists of the receptor. However, the pairing of GPR18 with NAGly and Δ9-tetrahydrocannabinol was not reproduced in two studies based on β-arrestin assays [15,18]. For further discussion, see [5] and [1].
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune system development
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
Gq/G11 family
Comments:  One study has indicated that GPR18 may be constitutively active [13].
References:  8,16
Tissue Distribution Click here for help
Spleen, testis, thymus, peripheral leukocytes, small intestine, appendix, lymph node
Species:  Human
Technique:  Northern blot
References:  6
Microglia
Species:  Human
Technique:  Immunocytochemistry
References:  11
BV2 microglial cells
Species:  Human
Technique:  Microarray analysis
References:  7
Lung, ovary, testis, thymus, striatum, hypothalamus, thyroid, peripheral blood leukocytes, cerebellum, brain stem
Species:  Mouse
Technique:  RT-PCR
References:  17
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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Functional Assays Click here for help
NAGly drives cellular migration at subnanomolar concentrations in both BV-2 microglia and HEK293 GPR18 transfected cells
Species:  Human
Tissue:  BV-2 microglia and HEK293 cell lines
Response measured:  Increased GPR18 mRNA expression and cell migration
References:  11
NAGly promotes apoptosis and resolution of inflammation via GPR18
Species:  Human
Tissue:  HEK-293 cell line
Response measured:  Increased PGJ, LXA4 and Trypan Blue response indicative of programmed cell death
References:  4
N-arachidonoyl glycine induces apoptosis via GPR18 in mouse macrophage derived cell line RAW264.7
Species:  Mouse
Tissue:  RAW264.7 Macrophage cell line
Response measured:  Reduced cell viability
References:  16
Δ9-tetrahydrocannabinol promotes endometrial HEC1B cell migration
Species:  Human
Tissue:  Endometrium
Response measured:  Cell migration
References:  4
Functional Assay Comments
Expression of GPR18 mRNA, TNF-α and IL-6 were markedly increased when mouse peritoneal macrophages were treated for differentiation to M1. Consequently, NAGly strongly induced apoptosis in highly GPR18 mRNA-expressing macrophages, while apoptotic effects were not as robust in less GPR18 mRNA-expressing macrophages which were treated for differentiation to M2 [16].
Physiological Functions Comments
In pancreatic beta cells NAGly causes intracellular Ca2+ mobilisation and insulin release. If this is via GPR18 activation a cooperative mechanism with L-type voltage gated ion channels could be implied [2].
Physiological Consequences of Altering Gene Expression Click here for help
Knockdown of GPR18 mRNA attenuates apoptosis by NAGly
Species:  Mouse
Tissue:  Macrophage
Technique:  RNAi
References:  16
Receptor knockdown enhances apoptosis in human melanoma cell lines
Species:  Human
Tissue:  Melanoma cell line
Technique:  RNA interference
References:  13
Overexpression of GPR18 affects directed migration induced by NAGly
Species:  Human
Tissue:  HEK293 cells
Technique:  Gene over-expression
References:  11
Physiological Consequences of Altering Gene Expression Comments
Studies are currently awaiting availibility of GPR18-/- animals [10].
Gene Expression and Pathophysiology Comments
GPR18 is abundantly overexpressed and constitutively active, inhibiting apoptosis, in all melanoma metastases [13].
General Comments
GPR18 has close affinity with EBI2 in view of their close chromosomal proximity and similar receptor expression patterns, suggesting that GPR18 and EBI2 may have similar biologic functions [3].

References

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1. Alexander SP. (2012) So what do we call GPR18 now?. Br J Pharmacol, 165 (8): 2411-3. [PMID:22014123]

2. Bradshaw HB, Lee SH, McHugh D. (2009) Orphan endogenous lipids and orphan GPCRs: a good match. Prostaglandins Other Lipid Mediat, 89 (3-4): 131-4. [PMID:19379823]

3. Brown DG, Sanderson MR, Garman E, Neidle S. (1992) Crystal structure of a berenil-d(CGCAAATTTGCG) complex. An example of drug-DNA recognition based on sequence-dependent structural features. J Mol Biol, 226 (2): 481-90. [PMID:1640462]

4. Burstein SH, McQuain CA, Ross AH, Salmonsen RA, Zurier RE. (2011) Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem, 112 (11): 3227-33. [PMID:21732409]

5. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]

6. Gantz I, Muraoka A, Yang YK, Samuelson LC, Zimmerman EM, Cook H, Yamada T. (1997) Cloning and chromosomal localization of a gene (GPR18) encoding a novel seven transmembrane receptor highly expressed in spleen and testis. Genomics, 42 (3): 462-6. [PMID:9205118]

7. Juknat A, Pietr M, Kozela E, Rimmerman N, Levy R, Coppola G, Geschwind D, Vogel Z. (2012) Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol, 165 (8): 2512-28. [PMID:21542829]

8. Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M. (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun, 347 (3): 827-32. [PMID:16844083]

9. Mahardhika AB, Załuski M, Schoeder CT, Boshta NM, Schabikowski J, Perri F, Łażewska D, Neumann A, Kremers S, Oneto A et al.. (2024) Potent, Selective Agonists for the Cannabinoid-like Orphan G Protein-Coupled Receptor GPR18: A Promising Drug Target for Cancer and Immunity. J Med Chem, 67 (12): 9896-9926. [PMID:38885438]

10. McHugh D. (2012) GPR18 in microglia: implications for the CNS and endocannabinoid system signalling. Br J Pharmacol, 167 (8): 1575-82. [PMID:22563843]

11. McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB. (2010) N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci, 11: 44. [PMID:20346144]

12. McHugh D, Page J, Dunn E, Bradshaw HB. (2012) Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol, 165 (8): 2414-24. [PMID:21595653]

13. Qin Y, Verdegaal EM, Siderius M, Bebelman JP, Smit MJ, Leurs R, Willemze R, Tensen CP, Osanto S. (2011) Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target. Pigment Cell Melanoma Res, 24 (1): 207-18. [PMID:20880198]

14. Schoeder CT, Mahardhika AB, Drabczyńska A, Kieć-Kononowicz K, Müller CE. (2020) Discovery of Tricyclic Xanthines as Agonists of the Cannabinoid-Activated Orphan G-Protein-Coupled Receptor GPR18. ACS Medicinal Chemistry Letters, Articles ASAP. DOI: 10.1021/acsmedchemlett.0c00208

15. 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]

16. Takenouchi R, Inoue K, Kambe Y, Miyata A. (2012) N-arachidonoyl glycine induces macrophage apoptosis via GPR18. Biochem Biophys Res Commun, 418 (2): 366-71. [PMID:22266325]

17. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC et al.. (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA, 100 (8): 4903-8. [PMID:12679517]

18. Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

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