Nomenclature: GPR18

Family: Class A Orphans

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

Contents

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 6
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
GPCRW
N-arachidonoyol glycine receptor
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
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
N-arachidonoylglycine
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 7.35 – 7.7 pEC50 11
pEC50 7.35 – 7.7 (EC50 2x10-8 – 4.45x10-8 M) [11]
O-1602 Hs Agonist 7.19 pEC50 11
pEC50 7.19 (EC50 6.53x10-8 M) [11]
abnormal cannabidiol Hs Agonist 6.08 pEC50 11
pEC50 6.08 (EC50 8.357x10-7 M) [11]
Δ9-tetrahydrocannabinol Hs Full agonist 6.02 pEC50 1,11
pEC50 6.02 (EC50 9.6x10-7 M) [1,11]
anandamide Hs Full agonist 5.42 pEC50 11
pEC50 5.42 (EC50 3.83x10-6 M) [11]
arachidonylcyclopropylamide Hs Agonist 4.87 pEC50 11
pEC50 4.87 (EC50 1.35x10-5 M) [11]
cannabidiol Hs Partial agonist 4.29 pEC50 11
pEC50 4.29 (EC50 5.11x10-5 M) [11]
AM251 Hs Partial agonist 4.02 pEC50 11
pEC50 4.02 (EC50 9.64x10-5 M) [11]
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. [10-11] 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 [13,16]. For further discussion, see [5] and [1].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Comments:  One study has indicated that GPR18 may be constitutively active [12].
References:  8,14
Tissue Distribution
Spleen, testis, thymus, peripheral leukocytes, small intestine, appendix, lymph node
Species:  Human
Technique:  Northern blot
References:  6
Microglia
Species:  Human
Technique:  Immunocytochemistry
References:  10
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:  15
Expression Datasets

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!
Functional Assays
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:  10
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:  14
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 [14].
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
Knockdown of GPR18 mRNA attenuates apoptosis by NAGly
Species:  Mouse
Tissue:  Macrophage
Technique:  RNAi
References:  14
Receptor knockdown enhances apoptosis in human melanoma cell lines
Species:  Human
Tissue:  Melanoma cell line
Technique:  RNA interference
References:  12
Overexpression of GPR18 affects directed migration induced by NAGly
Species:  Human
Tissue:  HEK293 cells
Technique:  Gene over-expression
References:  10
Physiological Consequences of Altering Gene Expression Comments
Studies are currently awaiting availibility of GPR18-/- animals [9].
Gene Expression and Pathophysiology Comments
GPR18 is abundantly overexpressed and constitutively active, inhibiting apoptosis, in all melanoma metastases [12].
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 β-Arrestin Orphan GPCR Cell Line (Cat no. 93-0560C2A)
PathHunter® eXpress GPR18 CHO-K1 β-Arrestin Orphan GPCR Assay (Cat no. 93-0560E2ACP1M)
more info

REFERENCES

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. Genomics42 (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. McHugh D. (2012) GPR18 in Microglia: implications for the CNS and endocannabinoid system signalling. Br J Pharmacol,  [Epub ahead of print]. [PMID:22563843]

10. 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 Neurosci11: 44. [PMID:20346144]

11. 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]

12. 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]

13. 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 Screen18 (5): 599-609. [PMID:23396314]

14. 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]

15. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA. (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A100: 4903-4908. [PMID:12679517]

16. 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 Chem284: 12328-12338. [PMID:19286662]

To cite this database page, please use the following:

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR18. Last modified on 26/11/2013. Accessed on 29/08/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=89.

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