The discovery of receptors with high-affinity for cannabinoids propelled a series of findings shortly thereafter that elucidated the basic components of the EC system (figure 1; for a comprehensive review see Kano et al., 2009). The membrane-lipid derived EC transmitters fall into two categories: ethanolamides (Devane et al., 1992; Hanus et al., 1993) and monoacylglycerols (Mechoulam et al., 1995; Sugiura et al., 1995). The most well studied of the ethanolamide transmitters, arachidonyl ethanolamide (anandamide; AEA), is derived from phosphatidyl ethanolamine precursors via N-acyl transferase and an N-acyl phosphatidyl ethanolamine (NAPE) specific isoform of phospholipase D (NAPE-PLD; Leung et al., 2006; Okamoto et al., 2004; Schmid, 2000). However, other pathways of AEA synthesis exist including sequential deacylation of NAPE by α, β hydrolase 4 (ABHD4; Liu et al., 2008) and a two-step hydrolysis by phospholipase A2 (PLA2) and lyso-phospholipase D (Cadas et al., 1996; Sun et al., 2004).
