NAGly receptor

N-Arachidonyl glycine receptor (NAGly receptor), also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene.^[5][6] Along with the other previously orphan receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors.^[7][8][9] It has been found to be involved in the regulation of intraocular pressure.^[10]

GPR18
Identifiers
Aliases	GPR18, G protein-coupled receptor 18
External IDs	OMIM: 602042; MGI: 107859; HomoloGene: 18814; GeneCards: GPR18; OMA:GPR18 - orthologs
Gene location (Human) Chr. Chromosome 13 (human)[1] Band 13q32.3 Start 99,254,732 bp[1] End 99,261,744 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 E5|14 65.86 cM Start 122,148,665 bp[2] End 122,153,193 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm gonad lymph node testicle granulocyte epithelium of nasopharynx tonsil blood appendix spleen Top expressed in mesenteric lymph nodes spleen blood subcutaneous adipose tissue morula thymus granulocyte embryo jejunum white adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function signal transducer activity G protein-coupled receptor activity Cellular component integral component of membrane plasma membrane membrane integral component of plasma membrane cytoplasmic vesicle membrane cytoplasmic vesicle Biological process signal transduction CD8-positive, alpha-beta intraepithelial T cell differentiation negative regulation of tumor necrosis factor production CD8-positive, gamma-delta intraepithelial T cell differentiation negative regulation of leukocyte chemotaxis T cell differentiation positive regulation of Rho protein signal transduction positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2841 110168 Ensembl ENSG00000125245 ENSMUSG00000050350 UniProt Q14330 Q8K1Z6 RefSeq (mRNA) NM_001098200 NM_005292 NM_182806 RefSeq (protein) NP_001091670 NP_005283 NP_877958 Location (UCSC) Chr 13: 99.25 – 99.26 Mb Chr 14: 122.15 – 122.15 Mb PubMed search [3] [4]
Wikidata
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Research supports the hypothesis that GPR18 is the abnormal cannabidiol receptor and N-arachidonoyl glycine, the endogenous lipid metabolite of anandamide, initiates directed microglial migration in the CNS through activation of GPR18,^[11] though recent evidence demonstrates that NAGly was not shown to be a GPR18 agonist in rat sympathetic neurons.^[12]

Resolvin D2 (RvD2), a member of the specialized proresolving mediators (SPM) class of polyunsaturated fatty acid metabolites, is an activating ligand for GPR18; RvD2 and its activation of GPR18 contribute to the resolution of inflammatory responses as well as inflammation-based and other diseases in animal models and are proposed to do so in humans.^[13] Furthermore, RvD2 is a metabolite of the omega-3 fatty acid, docosahexaenoic acid (DHA); the metabolism of DHA to RvD2 and RvD2's activation of GPR18 is proposed to one among many other mechanisms for the anti-inflammatory and other beneficial effects attributed to omega-3 fatty acid-rich diets^[14]

Ligands

Agonists

Ligands found to bind to GPR18 as agonists include:^[11][15]

• N-Arachidonoylglycine (NAGly)
• Abnormal cannabidiol (Abn-CBD)
• AM-251 - partial agonist
• Cannabidiol - partial agonist
• CBG-DMH^[16]
• O-1602
• Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) - THC is actually a more potent agonist at GPR18 than at CB₁ or CB₂, with Ki of 0.96nM at GPR18, 8.1nM at GPR55, 25.1nM at CB₁ and 35.2nM at CB₂.^[17]
• Anandamide (N-arachidonoyl ethanolamine, AEA)
• Arachidonylcyclopropylamide (ACPA)^[18]
• Resolvin D2 (RvD2) ^[19][20]
• PSB-KD107
• PSB-KK1415

Antagonists

• Amauromine^[21]
• O-1918
• PSB-CB5^[22]