Departments of Chemistry, Cell Biology, and Neuropharmacology
The Scripps Research Institute, La Jolla, California 92037, USA
e previously reported the isolation of a small molecule that accumulated selectively in the cerebrospinal fluid of sleep de-prived cats. We identified the endogenous compound as cis-9-octade-cenamide (oleamide), a member of a growing family of lipid signaling molecules, the fatty acid amides. Synthetic oleamide induced sleep when injected into rats, while structural analogs like oleic acid and trans-9-octadecenamide did not display sleep-inducing properties Oleamide has also been shown to affect serotonergic systems and block gap junction communication in glial cells, biological properties again not replicated by oleic acid and trans-9-octadece-namide. In our initial studies, we also identified a membrane bound enzymatic activity that hydrolyzes oleamide to its inactive acid, oleic acid. Employing an inhibitor-based affinity chromatography approach, we have isolated, cloned, and expressed this enzyme activity from rat liver plasma membranes. The RNA for this enzyme is expressed at high levels in liver and brain, with lower quantities of transcript found in spleen, lung, kidney, and testes. This transcript was not detectable in either heart or skeletal muscle, consistent with biochemical studies identifying no oleamide hydrolase enzyme activity in these two tissues. Additionally, we found that this enzyme activity also hydrolyzes anandamide, a fatty acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that the enzyme may serve as the general inactivating enzyme for the fatty acid amide family of signaling molecules. We therefore now refer to oleamide hydrolase as fatty acid amide hydrolase (FAAH), in recognition of the plurality of fatty acid amides that the enzyme can accept as substrates. Studies are presently underway to determine what role(s) FAAH may play in modulating the biological activities of oleamide.
