Anandamide precursors

The anandamide precursor, phosphatidylethanol amine, is present in membranes almost always accompanied by phophatidylserine. It seemed reasonable to expect the formation of anandamide from its precursor will be paralleled by formation of N-arachidinoylserine from phosphatidyl serine. Indeed, A -arachidonoyl-L-serine (ARA-S) was found to be formed alongside anandamide (Fig. 4). This compound was isolated from bovine brain and its structure was elucidated by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to the known cannabinoid CBi and CB2 or vanilloid TRPVl receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric... 

Fig. 3. Identification of anandamide precursors. Representative MSn spectra of anandamide precursor, NAPE extracted from biological samples.

Orgado et al, 2003), (ii) exogenous anandamide reduced ouabain-induced neuronal damage in 1- and 7-day-old rat pups through activation of CB1 receptors (van der Stelt et al., 2001), and (iii) a dramatic increase of anandamide precursors has been observed in the infant rat brain after head trauma (Hansen et al., 2001). 

Hansen, H.H., Ikonomidou, C., Bittigau, R, Hansen, S.H., and Hansen, H.S. (2001) Accumulation of the anandamide precursor and other Al-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death. Journal of Neurochemistry 76 39-46. 

Fernandez-Espejo, E., Caraballo, I., Rodrigez de Fonseca, E, Ferrer, B., El Banoua, E, Hores, J.A. and Galan-Rodrlgez, B. (2004) Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404 a modulator of endocaimabinoid function, Neurospychopharmacol-ogy, 29 1134-1142. 

Based on the pathways just proposed for the biosynthesis of anandamide and 2-AG, the formation of these endogenous ligands must also be dependent on the composition of the precursor lipids. This dependence is of greater importance for anandamide rather than for 2-AG because... 

Anandamide is believed to be synthesized from a phospholipid precursor, /V-arachidonoyl-phosphatidylethanolamine, catalysed by phospholipase D (Di Marzo et al. 1998). The other proposed route of synthesis is from condensation of arachidonic acid and ethanolamine, although this has yet to be demonstrated in living cells. 2-AG is formed in a calcium-dependent manner, and mediated by the enzymes phospholipase C and diacylglycerol lipase (Kondo et al. 1998 Stella et al. 1997). 

The endocannabinoid system is constituted of various lipid species, which include precursors and metabolites of anandamide and 2-AG (Figs. 1 and 2). Each of these lipids appears to have functionally distinct biosynthetic pathways and... 

Alternative biosynthetic pathways can interconvert NAPE precursors into other anandamide-containing lipids whose biological activities remain unknown. We recently observed that the combination of soft ionization techniques such as... 

As in the case of anandamide, 2-AG is derived from the hydrolysis of complex membrane lipids. The direct precursors of 2-AG can either be 1-acyl, 2-arachidonoyl-diacylglycerols (DAGs) or 2-arachidonoyl-lysoglycerophospholi-pids (e.g., lysophosphatidic acid, LPA). 

Simon, G. M., and Cravatt, B. F. (2008). Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-jV-acyl ethanolamine precursors in mouse brain. J. Biol. Chem. 283, 9341. 

Basavarajappa, B.S. and Hungund, B.L. (1999) Chronic ethanol increases the cannabinoid receptor agonist anandamide and its precursor Al-arachidonoylphosphatidylethanolamine in SK-N-SH cells. Journal of Neurochemistry 72 522-528. 

Pathway B is simply the reverse of the inaetivation reaction for anandamide and is also mediated by fatty aeid amide hydrolase (FAAH). Arguments have been raised against the physiological importance of this route because of the high concentrations of precursors required when studied in vitro. The events responsible for the initiation of anandamide production in vivo are not very well understood at this time, and much work remains to be done in this area. 

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