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 GPR18gene.[1][2] 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.[3][4][5]
Research supports the hypothesis that GPR18 is the abnormal cannabidiol receptor and N-arachidonoyl glycine, the endogenous lipid metabolite of anandamide, initiates directed microglialmigration in the CNS through activation of GPR18,[6] though recent evidence demonstrates that NAGly was not shown to be a GPR18 agonist in rat sympathetic neurons.[7]
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.[8] 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[9]
Ligands
Agonists
Ligands found to bind to GPR18 as agonists include:[6][10]
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.[11]
↑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.
↑Shinohara M, Serhan CN (2016). "Novel Endogenous Proresolving Molecules:Essential Fatty Acid-Derived and Gaseous Mediators in the Resolution of Inflammation". Journal of Atherosclerosis and Thrombosis. 23 (6): 655–64. doi:10.5551/jat.33928. PMID27052783.
↑Calder PC (2015). "Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance". Biochimica et Biophysica Acta. 1851 (4): 469–84. doi:10.1016/j.bbalip.2014.08.010. PMID25149823.
↑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. endoCANNABINOIDS: actions at non-CB1/CB2 cannabinoid receptors. New York: Springer. ISBN978-1-4614-4668-2.
↑Rempel, V; 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: 632–649. doi:10.1039/C3MD00394A.
Further reading
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.
