RT Journal Article SR Electronic T1 N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 213 OP 224 DO 10.1124/mol.108.045997 VO 74 IS 1 A1 Neta Rimmerman A1 Heather B. Bradshaw A1 H. Velocity Hughes A1 Jay Shih-Chieh Chen A1 Sherry Shu-Jung Hu A1 Douglas McHugh A1 Eivind Vefring A1 Jan A. Jahnsen A1 Eric L. Thompson A1 Kim Masuda A1 Benjamin F. Cravatt A1 Sumner Burstein A1 Michael R. Vasko A1 Anne L. Prieto A1 David K. O'Dell A1 J. Michael Walker YR 2008 UL http://molpharm.aspetjournals.org/content/74/1/213.abstract AB N-arachidonoyl glycine is an endogenous arachidonoyl amide that activates the orphan G protein-coupled receptor (GPCR) GPR18 in a pertussis toxin (PTX)-sensitive manner and produces antinociceptive and antiinflammatory effects. It is produced by direct conjugation of arachidonic acid to glycine and by oxidative metabolism of the endocannabinoid anandamide. Based on the presence of enzymes that conjugate fatty acids with glycine and the high abundance of palmitic acid in the brain, we hypothesized the endogenous formation of the saturated N-acyl amide N-palmitoyl glycine (PalGly). PalGly was partially purified from rat lipid extracts and identified using nano-high-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry. Here, we show that PalGly is produced after cellular stimulation and that it occurs in high levels in rat skin and spinal cord. PalGly was up-regulated in fatty acid amide hydrolase knockout mice, suggesting a pathway for enzymatic regulation. PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn. In addition, PalGly induced transient calcium influx in native adult dorsal root ganglion (DRG) cells and a DRG-like cell line (F-11). The effect of PalGly on the latter cells was characterized by strict structural requirements, PTX sensitivity, and dependence on the presence of extracellular calcium. PalGly-induced calcium influx was blocked by the nonselective calcium channel blockers ruthenium red, 1-(β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole (SK&F96365), and La3+. Furthermore, PalGly contributed to the production of NO through calcium-sensitive nitric-oxide synthase enzymes present in F-11 cells and was inhibited by the nitric-oxide synthase inhibitor 7-nitroindazole. The American Society for Pharmacology and Experimental Therapeutics