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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.108.045997v1 mol.108.045997v2 74/1/213    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rimmerman, N. Articles by Walker, J. M. Search for Related Content PubMed PubMed Citation Articles by Rimmerman, N. Articles by Walker, J. M.

N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons

Department of Psychological and Brain Sciences (N.R., H.B.B., H.V.H., J.S.-C.C., S.S.-J.H., D.M., E.V., J.A.J., A.L.P., J.M.W.), The Gill Center for Biomolecular Sciences (N.R., H.B.B., H.V.H., J.S.-C.C., S.S.-J.H., D.M., E.V., J.A.J., D.K.O., J.M.W.), and the Kinsey Institute for Research in Sex, Gender and Reproduction (H.B.B.), Indiana University, Bloomington, Indiana; Department of Chemical Physiology, The Scripps Institute, La Jolla, California (K.M., B.F.C.); Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana (E.L.T., M.R.V.); and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts (S.B.)

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.

Address correspondence to: Dr. Heather B. Bradshaw, 1101 East 10th St. Bloomington, IN 47405. E-mail: hbbradsh{at}indiana.edu