Metabolism by FAAH
Fig. 1. Metabolism of endogenous cannabinoids. N-APE, N-arachidonyl phosphatidyl ethanolamine; PLD, phospholipase D; IDG, inositol-1,2-diacylglycerol; PLC, phos-pholipase C; 2-AG, 2-arachidonoyl glycerol; FAAH, fatty acid amide hydrolase.
to a certain extent, 2-AG, but are still unclear for noladin ether. Anandamide and 2-AG are produced from cleavage of two different phospholipid precursors present in the cell membranes of neurons and immune cells in particular. Anandamide is synthesized from the membrane phospholipid N-arachidonyl phosphatidylethanolamine by a phosphodiesterase called phospholipase D, an enzyme stimulated by depolarization-induced increase in intracellular Ca2+ (5,6). The synthetic pathway is also indirectly stimulated by cyclic adenosine monophosphate (cAMP)/protein kinase A, indicating possible receptor-mediated mechanisms (7,8). Anandamide amounts of 10-50 pmol/g of brain tissue have been reported (6). 2-AG is mainly the product of phospholipase C digestion of inositol-1, 2-diacylglycerol and, interestingly, is much more abundant than anandamide, with amounts ranging from 2 to 10 nmol/g of tissue (9). The synthesis of 2-AG is also calcium-dependent (4). An interesting feature of anandamide and 2-AG is the "on-demand" synthesis and release of these lipids, possibly not from vesicles, differentiating the endocannabinoids from classical neurotransmitters—hence the term "modulator" (10). Anandamide is then known to be transported into cells by carrier-mediated uptake, which does not depend on sodium or adenosine-5'-triphos-phate (ATP), another difference from classical neurotransmitters, but similar to the structurally related prostaglandin E2 (11). This transporter participates in the inactiva-tion of anandamide. Both anandamide and 2-AG are known to be rapidly hydrolyzed by the intracellular enzyme fatty acid amide hydrolase (FAAH) (6,12,13).
Endocannabinoids may function physiologically as retrograde synaptic messengers (Fig. 2) (14,15). When a postsynaptic neuron is strongly depolarized, it synthesizes and releases endocannabinoids through a nonvesicular mechanism. These molecules, in turn, bind the presynaptic neuron at CB1 receptors and inhibit its neu-rotransmitter release. It is a form of negative feedback. The chemical nature of the presynaptic neuron is important. If the release of an inhibitory transmitter like y-aminobutyric acid (GABA) is decreased, it is called in electrophysiology depolarization-induced suppression of inhibition (DSI) and would result in exacerbation of postsynaptic transmission. If the release of an excitatory neurotransmitter like glutamate
is decreased, it is referred to as depolarization-induced suppression of excitation (DSE), and would diminish postsynaptic transmission. Several studies argue in favor of this physiological role of anandamide and other endogenous cannabinoids (16-18). Both DSI and DSE depend on rises in calcium and on Gi proteins, which are also necessary for the synthesis and release of endogenous cannabinoids and a feature of their receptors. DSI and DSE are antagonized by rimonabant, a selective CBj receptor antagonist. And finally, CBj stimulation inhibits GABA release from hippocampal interneurons (which synapse with the important pyramidal neurons) and glutamate from cerebellar basket cells (which synapse with Purkinje neurons).
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