NAGly receptor explained

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.^{[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]} It has been found to be involved in the regulation of intraocular pressure.^[6]

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, 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

AgonistsLigands found to bind to GPR18 as agonists include:^{[10] [11]}

• N-Arachidonoylglycine (NAGly)
• Abnormal cannabidiol (Abn-CBD)
• AM-251 - partial agonist
• Cannabidiol - partial agonist
• CBG-DMH^[12]
• 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.^[13]
• Anandamide (N-arachidonoyl ethanolamine, AEA)
• Arachidonylcyclopropylamide (ACPA)^[14]
• Resolvin D2 (RvD2) ^[15]

Antagonists

• Amauromine^[16]
• O-1918
• CID-85469571^[17]

Further reading

• Christian SL, McDonough J, Liu Cy CY, Shaikh S, Vlamakis V, Badner JA, Chakravarti A, Gershon ES . 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 . 2002 . 11991713 . 10.1006/geno.2002.6765 .
• Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M . Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18 . Biochem. Biophys. Res. Commun. . 347 . 3 . 827–32 . 2006 . 16844083 . 10.1016/j.bbrc.2006.06.175 .

Notes and References

1. Gantz I, Muraoka A, Yang YK, Samuelson LC, Zimmerman EM, Cook H, Yamada T . 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 . Sep 1997 . 9205118 . 10.1006/geno.1997.4752 .
2. Web site: Entrez Gene: GPR18 G protein-coupled receptor 18 .
3. Kohno M, Hasegawa H, Inoue A, Muraoka M, Miyazaki T, Oka K, Yasukawa M . Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18 . Biochem. Biophys. Res. Commun. . 347 . 3 . 827–32 . September 2006 . 16844083 . 10.1016/j.bbrc.2006.06.175 .
4. Burstein S . The elmiric acids: biologically active anandamide analogs . Neuropharmacology . 55 . 8 . 1259–64 . December 2008 . 18187165 . 2621443 . 10.1016/j.neuropharm.2007.11.011 .
5. Bradshaw HB, Lee SH, McHugh D . Prostaglandins Other Lipid Mediat. . 89 . 3–4 . 131–4 . September 2009 . 19379823 . 2740803 . 10.1016/j.prostaglandins.2009.04.006 . Orphan endogenous lipids and orphan GPCRS: A good match .
6. Caldwell MD, Hu SS, Viswanathan S, Bradshaw H, Kelly ME, Straiker A . A GPR18-based signalling system regulates IOP in murine eye . British Journal of Pharmacology . 169 . 4 . 834–43 . June 2013 . 23461720 . 3687663 . 10.1111/bph.12136 .
7. Lu VB, Puhl HL, Ikeda SR . N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. . Molecular Pharmacology . 83 . 1 . 267–82 . Jan 2013 . 23104136 . 10.1124/mol.112.081182 . 3533477.
8. Shinohara M, Serhan CN . 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 . 2016 . 27052783 . 10.5551/jat.33928 . 7399282 . free .
9. Calder PC . 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 . 2015 . 25149823 . 10.1016/j.bbalip.2014.08.010 .
10. McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM, Bradshaw HB . N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor . BMC Neurosci . 11 . 44 . 2010 . 20346144 . 2865488 . 10.1186/1471-2202-11-44 . free .
11. McHugh D, Page J, Dunn E, Bradshaw HB . 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 . 165 . 8 . 2414–24 . May 2011 . 21595653 . 10.1111/j.1476-5381.2011.01497.x . 3423258 .
12. Szczesniak AM, Maor Y, Robertson H, Hung O, Kelly ME . 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 . October 2011 . 21770780 . 10.1089/jop.2011.0041 .
13. Ashton JC . The atypical cannabinoid o-1602: Targets, actions, and the central nervous system . Central Nervous System Agents in Medicinal Chemistry . 12 . 3 . 233–239 . 2012 . 22831390 . 10.2174/187152412802430156 .
14. Book: Abood ME . endoCANNABINOIDS: actions at non-CB1/CB2 cannabinoid receptors . 2012 . Springer . New York . 978-1-4614-4668-2 . McHugh D, Bradshaw HB . GPR18 and NAGly Signaling: New Members of the Endocannabinoid Family or Distant Cousins? .
15. Chiang N, Dalli J, Colas RA, Serhan CN . Identification of Resolvin D2 Receptor Mediating Resolution of Infections and Organ Protection . J. Exp. Med. . 212 . 8 . 1203–1217 . 2015 . 26195725 . 10.1084/jem.20150225 . 4516788.
16. Schoeder CT, Kaleta M, Mahardhika AB, Olejarz-Maciej A, Łażewska D, Kieć-Kononowicz K, Müller CE . 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 . July 2018 . 29902723 . 10.1016/j.ejmech.2018.05.050 . 49214747 .
17. Rempel V, Atzler K, Behrenswerth A, Karcz T, Schoeder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Müller CE . 6 . 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 . 10.1039/C3MD00394A .