Anandamide formation

Di Marzo V, Berrendero F, Bisogno T, Gonzalez S, Cavaliere P, Romero J, Cebeira M, Ramos JA, Fernandez-Ruiz J (2000b) Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of AO-tetrahydrocannabinol-tolerant rats. J Neurochem 74 1627-1635... 

Sasaki, T. and Chang, M.C. (1997) W-arachidonylethanolamine (anandamide) formation from N-arachido-nylphosphatidylethanolamine in rat brain membranes. Life Sciences 61 1803-1810. 

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... 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

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... 

Padgett, L. W., Howlett, A. C., Shim, J. Y. (2008) Binding mode prediction of con-formationally restricted anandamide analogs within the CB1 receptor. J Mol Signal 3, 5. 

Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372 686-91... 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

Piomelli, D. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372 686-91, 1994. 

Arreaza G, Devane WA, Omeir RL, Sajnani G, Kunz J, Cravatt BF, Deutsch DG (1997) The cloned rat hydrolytic enzyme responsible for die breakdown of anandamide also catalyzes its formation via die condensation of arachidonic acid and ethanolamine. Neurosci Lett 234 59-62... 

Weber A, Ni J, Ling KH, Acheampong A, Tang-Liu DD, Burk R, Cravatt BF, Woodward D (2004) Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry. J Lipid Res 45 757-763... 

Sagan S, Venance L, Torrens Y, Cordier J, Glowinski J, Giaume C (1999) Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CBl cannabinoid receptors in cultured astrocytes. Eur J Neurosci 11 691-699... 

The subsequent discovery of the endocannabinoids, arachidonoylethanolamine (anandamide) (Devane et al. 1992b Hanus et al. 1993) and 2-arachidonoyl glycerol (2-AG) (Di Marzo 1998 Mechoulam et al. 1995 Stella et al. 1997) has led to a better understanding of the physiological and biochemical roles of the endocannabinoid system. 2-Arachidonyl glyceryl ether, also known as noladin ether (Hanus et al. 2001), has been proposed as a representative of a third endocannabinoid class. However, noladin ether s pathway of formation has not been characterized and its occurrence in the normal brain has been questioned (Oka et al. 2003). 

Anandamide (arachidonoylethanolamide) is just one of a family of lipids known as W-acylethanolamines (NAEs), which are generated from membrane phospholipids via a common enzymatic pathway (see below). The occurrence of anandamide in an organism is dependent on (1) the presence of the fatty acid arachidonic acid as a component of membrane phospholipids and (2) the presence of enzymes that can catalyse formation of NAEs from membrane phospholipids. Therefore, the phylogenetic distribution of anandamide is likely to reflect a combination of both the phylogenetic distribution of arachidonic acid as a fatty acid component of membrane lipids and the phylogenetic distribution of the enzymes that can catalyse formation of NAEs. 

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