N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons

Neta Rimmerman, Heather B. Bradshaw, H. Velocity Hughes, Jay Shih Chieh Chen, Sherry Shu Jung Hu, Douglas McHugh, Eivind Vefring, Jan A. Jahnsen, Eric L. Thompson, Kim Masuda, Benjamin F. Cravatt, Sumner Burstein, Michael Vasko, Anne L. Prieto, David K. O'Dell, J. Michael Walker

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)213-224
Number of pages12
JournalMolecular Pharmacology
Volume74
Issue number1
DOIs
StatePublished - Jul 2008

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Sensory Receptor Cells
Glycine
Nitric Oxide
Lipids
Calcium
Pertussis Toxin
Spinal Ganglia
Amides
Nitric Oxide Synthase
lime
N-palmitoylglycine
Ruthenium Red
Endocannabinoids
Nociceptors
Palmitic Acid
Calcium Channel Blockers
Enzymes
G-Protein-Coupled Receptors
Arachidonic Acid
Knockout Mice

ASJC Scopus subject areas

  • Pharmacology

Cite this

Rimmerman, N., Bradshaw, H. B., Hughes, H. V., Chen, J. S. C., Hu, S. S. J., McHugh, D., ... Walker, J. M. (2008). N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons. Molecular Pharmacology, 74(1), 213-224. https://doi.org/10.1124/mol.108.045997

N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons. / Rimmerman, Neta; Bradshaw, Heather B.; Hughes, H. Velocity; Chen, Jay Shih Chieh; Hu, Sherry Shu Jung; McHugh, Douglas; Vefring, Eivind; Jahnsen, Jan A.; Thompson, Eric L.; Masuda, Kim; Cravatt, Benjamin F.; Burstein, Sumner; Vasko, Michael; Prieto, Anne L.; O'Dell, David K.; Walker, J. Michael.

In: Molecular Pharmacology, Vol. 74, No. 1, 07.2008, p. 213-224.

Research output: Contribution to journalArticle

Rimmerman, N, Bradshaw, HB, Hughes, HV, Chen, JSC, Hu, SSJ, McHugh, D, Vefring, E, Jahnsen, JA, Thompson, EL, Masuda, K, Cravatt, BF, Burstein, S, Vasko, M, Prieto, AL, O'Dell, DK & Walker, JM 2008, 'N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons', Molecular Pharmacology, vol. 74, no. 1, pp. 213-224. https://doi.org/10.1124/mol.108.045997
Rimmerman, Neta ; Bradshaw, Heather B. ; Hughes, H. Velocity ; Chen, Jay Shih Chieh ; Hu, Sherry Shu Jung ; McHugh, Douglas ; Vefring, Eivind ; Jahnsen, Jan A. ; Thompson, Eric L. ; Masuda, Kim ; Cravatt, Benjamin F. ; Burstein, Sumner ; Vasko, Michael ; Prieto, Anne L. ; O'Dell, David K. ; Walker, J. Michael. / N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons. In: Molecular Pharmacology. 2008 ; Vol. 74, No. 1. pp. 213-224.
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AU - Vefring, Eivind

AU - Jahnsen, Jan A.

AU - Thompson, Eric L.

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AU - Cravatt, Benjamin F.

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