Endocannabinoids Case

Endocannabinoids are a group of lipid messengers that act on specific cell surface receptors. The endocannabinoid system consists of two cannabinoid (CB) receptors, seven ligands, and ligand-catabolizing enzymes such as fatty

acid amid hydrolase (FAAH) and monoglyceride lipase (MGL). It is phylogenetically ancient, occurring in vertebrates and invertebrates (Fride)

The receptors were actually discovered before endocannabinoids because of their interaction on delta 9 - tetrahydrocannabinol (THC) the psychoactive component of Cannibis sativa, better known as marijuana. THC was not isolated until 1964 and endocannabinoids were not discovered until 1992 (Gaoni Mechoulam 1964; Devane 1992).

The ligands include anandamide (AEA), 2-arachidonoyl glycerol (2-AG) and noladin ether among others. CB1 and CB2 are the main receptors and belong to the family of 7-transmembrane-segment G protein coupled receptors (Hajos, Ledent et al.). CB1 is found in the central nervous system and female reproductive system while CB2 is restricted to the immune system (Pertwee). Among the signaling functions of these receptors are, inhibition of adenylate cyclase, the regulation of ionic currents, and the activation of focal adhesion kinase (FAK), mitogen activated protein (MAPK) (Maccarrone, Bari et al.). This suggests an involvement in the cell survival/cell death decision as well as the neuromodulation of neurotransmitters. FAAH and MGL are responsible for the degradation of AEA and 2-AG (Gaetani, Cuomo et al.).

AEA in particular has been the most studied endocannabinoid. It is produced on demand by receptor-stimulated cleavage of lipid precursors. Its' biological activity is inhibited by removal from the extracellular space by two mechanisms. First by degradation by FAAH and also by uptake through a high affinity transporter called AEA membrane transporter (AMT). Its biological consequences in apoptosis are complicated. In general it is thought to have antitumorogenic properties from is apoptotic role in glioma cells and lymphocyte proliferation (Maccarrone 2003). But it also has non apoptotic consequences via modulation of various signaling pathways, including the pathways of CB1, and including the phosphatidylinositol 3-kinase/protein kinase B pathway in human astrocytoma cells (Maccarrone 2003). In general it seems to have proapoptotic activity by binding to vanilloid receptors and antiapoptotic activity by binding cannabinoid receptors.

Although AEA's main effects are on the same receptors as THC, another receptor has been thrown in the mix. The vanilloid receptors mediation in the effects of AEA are well established.