PT  - JOURNAL ARTICLE
AU  - Neta Rimmerman
AU  - Heather B. Bradshaw
AU  - H. Velocity Hughes
AU  - Jay Shih-Chieh Chen
AU  - Sherry Shu-Jung Hu
AU  - Douglas McHugh
AU  - Eivind Vefring
AU  - Jan A. Jahnsen
AU  - Eric L. Thompson
AU  - Kim Masuda
AU  - Benjamin F. Cravatt
AU  - Sumner Burstein
AU  - Michael R. Vasko
AU  - Anne L. Prieto
AU  - David K. O'Dell
AU  - J. Michael Walker
TI  - <em>N</em>-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons
AID  - 10.1124/mol.108.045997
DP  - 2008 Jul 01
TA  - Molecular Pharmacology
PG  - 213--224
VI  - 74
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/74/1/213.short
4100  - http://molpharm.aspetjournals.org/content/74/1/213.full
SO  - Mol Pharmacol2008 Jul 01; 74
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