The biosynthesis and degradation of NaGly is not completely understood. Using biochemical approaches, two proposed pathways include: 1) enzymatic conjugation of arachidonic acid and glycine and 2) the oxidative metabolism of the endogenous cannabinoidanandamide.[8][9] In support of the former "direct" pathway of arachidonic acid and glycine conjugation and hydrolysis, the secreted enzymePM20D1 and the intracellular amidaseFAAH has been identified as enzymatic regulators of NAGly metabolism in mice.[10][11]
NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats.[12] In particular, peripherally administered NAGly inhibited phase 2 pain behavior, suggesting either a direct suppression of nociceptive afferents on the nerve or an indirect modulation of the afferents' interstitial environment.[12] In either case, these findings hold promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also effective in acute pain models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection ofFruend's complete adjuvant.[13] Similar mechanical allydonia induced by partial ligation of thesciatic nerve was also reduced by NaGly.[14] Other arachidonic acid-amino acid conjugates did not have the same effects and the actions of NaGly were not affected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid receptor mediated approach to alleviate inflammatory pain.[13][14]
NaGly was shown to be endogenous ligand for the G-protein couple receptor GPR92 along withfarnesyl pyrophosphate.[15] In thedorsal root ganglia (DRG), where GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role of NaGly in the sensory nervous system through the activation of GPR92.[15]
NAGly has been the focus of research on the immune system because of its antinociceptive effects and inhibitory action on components of the immune system. Specifically, it significantly inhibitedTNFα andIFNγ production, and it shows potential as a therapeutic treatment for chronic inflammation.[16] Moreover, NAGly has been shown to act as a substrate forcyclooxygenase-2 (COX-2), the enzyme primarily known for producingprostaglandins associated with increases in inflammation andhyperalgesia. In many mammalian tissues that express COX-2, significant levels of NAGly are naturally present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETE-Gly.[17]
NAGly has been hypothesized to induce cell migration in BV-2microglia cells.[5] The same research suggests that this migration occurs throughGPR18. This was verified using GPR18 transfectedHEK-293 cells. The same migration wasn't witnessed using non-transfected andGPR55 transfectedHEK-293.[5] Additionally,tetrahydrocannabinol and NaGly are fullagonists at the GPR18 receptors and induce migration in humanendometrial HEC-1B cells.[18] Understanding functions of NaGly in such structures provides a promising future in helping treat diseases such asendometriosis.
NAGly powerfully stimulates oxygen consumption in multiple cell lines, including murine C2C12 myoblasts and human HEK293T cells.[19] This respiratory bioactivity of NAGly is by increased uncoupled (state4u) mitochondrial respiration and depends on the presence of fatty acid desaturation.[20] NAGly respiration bioactivity can be also abrogated in the presence of serum albumin, which functions as an NAGly carrier in murine blood plasma.[21]
NaGly was identified as a novelinsulinsecretagogue and was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium channels.[22] Additionally, this action was dependent on extracellular glucose level.[22]
NaGly has been shown to inhibit theglycine transporter GLYT2a in a non-competitive fashion witharachidonic acid and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachidonyl amino acids, especially because other conjugated amino acids had similar effects.[23]
^Sheskin T, Hanus L, Slager J, Vogel Z, Mechoulam R (February 1997). "Structural requirements for binding of anandamide-type compounds to the brain cannabinoid receptor".Journal of Medicinal Chemistry.40 (5):659–67.doi:10.1021/jm960752x.PMID9057852.
^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".Biochemical and Biophysical Research Communications.347 (3):827–32.doi:10.1016/j.bbrc.2006.06.175.PMID16844083.
^WO application 9738688, Ferrante A, Poulos A, Pitt M, Easton C, Sleigh M, Rathjen D, Widmer F, "Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids", published 23 October 1997, assigned to Peptide Technology Pty Ltd. and Women's and Children's Hospital Adelaide
^Prusakiewicz JJ, Kingsley PJ, Kozak KR, Marnett LJ (August 2002). "Selective oxygenation of N-arachidonylglycine by cyclooxygenase-2".Biochemical and Biophysical Research Communications.296 (3):612–7.doi:10.1016/s0006-291x(02)00915-4.PMID12176025.
