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GPR18

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Clinically-Relevant Mutations and Pathophysiology
General Comments
References
Gene and Protein Information
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 5
Mouse 7 331 15q25 Gpr18 G protein-coupled receptor 18
Rat 7 331 15q25 Gpr18 G protein-coupled receptor 18
Previous and Unofficial Names
GPR18
G-protein coupled receptor 18
NAGly receptor
N-arachidonyl glycine receptor
GPCRW
Gpr18_predicted
LOC306191
LOC679957
MGC156838
G protein-coupled receptor 18
G protein-coupled receptor 18 (predicted)
similar to G protein-coupled receptor 18
Database Links
DrugBank Target 4056 (Hs)
Ensembl ENSG00000125245 (Hs), ENSMUSG00000050350 (Mm), ENSRNOG00000012628 (Rn)
Entrez Gene 2841 (Hs), 110168 (Mm), 306191 (Rn)
GeneCards GPR18 (Hs)
GenitoUrinary Development Molecular Anatomy Project Gpr18 (Mm)
HomoloGene 18814 (Hs)
Human Protein Reference Database 03621 (Hs)
InterPro Q14330 (Hs), Q8K1Z6 (Mm), A1A5S3 (Rn)
KEGG Gene hsa:2841 (Hs), mmu:110168 (Mm), rno:306191 (Rn)
OMIM 602042 (Hs)
PharmGKB Gene PA28860 (Hs)
PhosphoSitePlus Q14330 (Hs), Q8K1Z6 (Mm)
Protein Ontology (PRO) PRO:000001430 (Hs)
RefSeq Nucleotide NM_005292 (Hs), NM_182806 (Mm), NM_001079710 (Rn)
RefSeq Protein NP_005283 (Hs), NP_877958 (Mm), NP_001073178 (Rn)
TreeFam ENSG00000125245 (Hs), ENSMUSG00000050350 (Mm), ENSRNOG00000012628 (Rn)
UniGene Hs. 631765 (Hs)
UniProt Q14330 (Hs), Q8K1Z6 (Mm), A1A5S3 (Rn)
Wikipedia GPR18
GPR18, GPR55 and GPR119, Orphan and other 7TM receptors
Natural/Endogenous Ligand(s)
Δ9-tetrahydrocannabinol
N-arachidonoylglycine
Comments: Proposed ligands, single publication
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
N-arachidonoylglycine Hs Full agonist 7.7 – 7.35 pEC50 5,10
O-1602 Hs Agonist 7.19 pEC50 10
Δ9-tetrahydrocannabinol Hs Full agonist 6.02 pEC50 1,10
anandamide Hs Full agonist 5.42 pEC50 10
arachidonyl cyclopropylamide Hs Agonist 4.87 pEC50 10
cannabidiol Hs Agonist 4.29 pEC50 10
AM251 Hs Agonist 4.02 pEC50 10
Agonist Comments
A single study has found the reported ligand for GPR18, NAGly, to be inactive [14].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Comments:  A single study has indicated that GPR18 may be constitutively active [11].
References:  7,12
Tissue Distribution
Microglia
Species:  Human
Technique:  Immunocytochemistry
References:  9
BV2 microglial cells
Species:  Human
Technique:  Microarray analysis
References:  6
Spleen, testis, thymus, peripheral leukocytes, small intestine, appendix, lymph node
Species:  Human
Technique:  Northern blot
References:  5
Lung, ovary, testis, thymus, striatum, hypothalamus, thyroid, peripeheral blood leukocytes, cerebellum, brain stem
Species:  Mouse
Technique:  RT-PCR
References:  13
Expression Datasets

Click here to show/hide data

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
NAGly drives cellular migration at subnanomaolar 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:  9
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:  12
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 [12].
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
Receptor knockdown enhances apoptosis in human melanoma cell lines
Species:  Human
Tissue:  Melanoma cell line
Technique:  RNA interference
References:  11
Overexpression of GPR18 affects directed migration induced by NAGly
Species:  Human
Tissue:  HEK293 cells
Technique:  Gene over-expression
References:  9
Knockdown of GPR18,/i> mRNA attenuates apoptosis by NAGly
Species:  Mouse
Tissue:  Macrophage
Technique:  RNAi
References:  12
Physiological Consequences of Altering Gene Expression Comments
Studies are currently awaiting availibility of GPR18-/- animals [8].
Clinically-Relevant Mutations and Pathophysiology
Comments:  GPR18 is abundantly overexpressed and constitutively active, inhibiting apoptosis, in all melanoma metastases.
References:  11
Mutations not determined
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].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR18 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0560C2A
DiscoveRx PathHunter® eXpress GPR18 CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0560E2ACP1

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. 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]

6. 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]

7. 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]

8. McHugh, D. (2012) GPR18 in Microglia: implications for the CNS and endocannabinoid system signalling. Br J Pharmacol,  [Epub ahead of print]. [PMID:22563843]

9. 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]

10. McHugh, D; Page, J; Dunn, E; Bradshaw, HB. (2011) Δ(9) -THC and N-arachidonyl glycine are full agonists at GPR18 and cause migration in the human endometrial cell line, HEC-1B. Br J Pharmacol,  [Epub ahead of print]. [PMID:21595653]

11. Qin, Y; Verdegaal, EM; Siderius, M; Bebelman, JP; Smit, MJ; Leurs, R; Willemze, R; Tensen, CP; Osanto, S. (2010) 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,  [Epub ahead of print]. [PMID:20880198]

12. 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]

13. Vassilatis, D. K., Hohmann, J. G., Zeng, H., Li, F., Ranchalis, J. E., Mortrud, M. T., Brown, A., Rodriguez, S. S., Weller, J. R., Wright, A. C., Bergmann, J. E. and Gaitanaris, G. A. (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A, 100: 4903-4908. [PMID:12679517]

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

To cite this database page, please use the following:

Amy E. Monaghan.
Class A Orphans: GPR18. Last modified on 12/09/2012. Accessed on 19/06/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=89.


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