FAAH-2

Fatty acid amide hydrolase 2 (FAAH-2) inactivates bioactive N-acylethanolamines, including anandamide (AEA) and palmitoylethanolamide (PEA), thereby regulating endocannabinoid lipid signaling^[1]. Mechanistically, FAAH-2 hydrolyzes AEA and PEA in intact cells and localizes to lipid droplets, distinguishing its spatial biology from endoplasmic-reticulum-localized FAAH^[1]. In human seminal vesicles and vas deferens, FAAH1 and FAAH2 transcripts and proteins were detected in epithelial cells, supporting a role in epithelial homeostasis or secretory function rather than smooth-muscle or nerve-fiber signaling^[2]. In Hirudo verbana, a FAAH-2 orthologue showed serine hydrolase activity, hydrolyzed a FAAH substrate, and was blocked by URB597, linking FAAH-2-like activity to endocannabinoid modulation of nociception-relevant synapses^[3]. Compared with FAAH, FAAH-2 contributes differently across species and models, because a FAAH-selective inhibitor that did not inhibit FAAH-2 elevated plasma fatty acid amides in rat, dog, and monkey^[4]. In zebrafish, disruption of faah2a attenuated locomotor responses to hyperosmotic stress, indicating that FAAH-2 biology can support stress-response studies in non-rodent vertebrates^[5].