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First published on April 18, 2008; DOI: 10.1124/mol.108.045997

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Received for publication February 6, 2008.
Revised April 16, 2008.
Accepted for publication April 17, 2008.

N-PALMITOYL GLYCINE, A NOVEL ENDOGENOUS LIPID THAT ACTS AS A MODULATOR OF CALCIUM INFLUX AND NITRIC OXIDE PRODUCTION IN SENSORY NEURONS

Neta Rimmerman 1, Heather B Bradshaw 2*, H Velocity Hughes 1, Jay S-C Chen 1, Sherry S-J Hu 1, Douglas McHugh 1, Evind Vefring 1, Jan A Jahnsen 1, Eric L Thompson 3, Kim Masuda 4, Benjamin F Cravatt 4, Sumner Burstein 5, Michael R Vasko 3, Anne L Prieto 1, David K O'Dell 1, Michael Walker 1

1 Indiana University 2 University of Indiana 3 Indiana University School of Medicine 4 Scripps Institute 5 University of Mass Worcester

* Address correspondence to: E-mail: hbbradsh{at}indiana.edu

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 anti-nociceptive and anti-inflammatory 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 (HPLC/QqTOF) mass spectrometry. Here we show that PalGly is produced following cellular stimulation and occurs in high levels in rat skin and spinal cord. PalGly was upregulated in fatty acid amide hydrlase (FAAH) Knockout (KO) 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 DRG cells and a DRG-like cell line (F-11). The effect of PalGly on the latter was characterized by strict structural requirements, PTX-sensitivity and dependence on the presence of extracellular calcium. PalGly-induced calcium influx was blocked by the non-selective calcium channel blockers ruthenium red, SKF96365 and La3+. Furthermore, PalGly contributed to the production of nitric oxide (NO) through calcium-sensitive nitric oxide synthase (NOS) enzymes present in F-11 cells, and was inhibited by the nitric oxide synthase inhibitor 7-NI.


Key words: Cannabinoid, Ion channel regulation, Calcium (G Protein Coupled Signals), Structure-activity relationships and modeling, Ca imaging, Fluorescence techniques, Mass Spectroscopy




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