N-Arachidonyl glycine receptor (NAGly receptor), also known asG protein-coupled receptor 18 (GPR18), is aprotein that in humans is encoded by theGPR18gene.[5][6] Along with the other previouslyorphan receptorsGPR55 andGPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind tocannabinoid receptors.[7][8][9] It has been found to be involved in the regulation ofintraocular pressure.[10]
Research supports the hypothesis that GPR18 is theabnormal cannabidiol receptor andN-arachidonoyl glycine, the endogenous lipid metabolite ofanandamide, initiates directedmicroglialmigration 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 thespecialized proresolving mediators (SPM) class ofpolyunsaturated 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 theomega-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]
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]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Gantz I, Muraoka A, Yang YK, Samuelson LC, Zimmerman EM, Cook H, Yamada T (Sep 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.doi:10.1006/geno.1997.4752.PMID9205118.
^Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M (September 2006). "Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18".Biochem. Biophys. Res. Commun.347 (3):827–32.doi:10.1016/j.bbrc.2006.06.175.PMID16844083.
^Calder PC (2015). "Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance".Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.1851 (4):469–84.doi:10.1016/j.bbalip.2014.08.010.PMID25149823.
^Szczesniak AM, Maor Y, Robertson H, Hung O, Kelly ME (October 2011). "Nonpsychotropic cannabinoids, abnormal cannabidiol and canabigerol-dimethyl heptyl, act at novel cannabinoid receptors to reduce intraocular pressure".Journal of Ocular Pharmacology and Therapeutics.27 (5):427–35.doi:10.1089/jop.2011.0041.PMID21770780.
^Ashton JC (2012). "The atypical cannabinoid o-1602: Targets, actions, and the central nervous system".Central Nervous System Agents in Medicinal Chemistry.12 (3):233–239.doi:10.2174/187152412802430156.PMID22831390.
^McHugh D, Bradshaw HB (2012). "GPR18 and NAGly Signaling: New Members of the Endocannabinoid Family or Distant Cousins?". In Abood ME (ed.).endoCANNABINOIDS: actions at non-CB1/CB2 cannabinoid receptors. New York: Springer.ISBN978-1-4614-4668-2.
^Schoeder CT, Kaleta M, Mahardhika AB, Olejarz-Maciej A, Łażewska D, Kieć-Kononowicz K, Müller CE (July 2018). "Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18".European Journal of Medicinal Chemistry.155:381–397.doi:10.1016/j.ejmech.2018.05.050.PMID29902723.S2CID49214747.
^Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, et al. (2014). "Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55".Med. Chem. Commun.5 (5):632–649.doi:10.1039/C3MD00394A.
Christian SL, McDonough J, Liu Cy CY, Shaikh S, Vlamakis V, Badner JA, Chakravarti A, Gershon ES (2002). "An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia".Genomics.79 (5):635–56.doi:10.1006/geno.2002.6765.PMID11991713.
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.doi:10.1016/j.bbrc.2006.06.175.PMID16844083.
