Fig 1.

Endocannabinoid signalling in the nervous system. 1, Endocannabinoids are manufactured ‘on demand’ in the postsynaptic terminals: AEA is generated from phospholipase-D (PLD)-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE) and 2-AG from diacylglycerol lipase (DAGL)-mediated hydrolysis of the membrane lipid diacylglycerol (DAG); 2, AEA and 2-AG diffuse retrograde towards the presynaptic terminals and bind to activate the presynaptic receptor CB₁; 3, binding of phytocannabinoid and endocannabinoid agonists to the CB₁ receptor triggers traditional G-protein-coupled signalling leading to decreased formation of adenosine 3ʹ,5ʹ-cyclic monophosphate and activity of protein kinase A; 4, activation of the CB₁ receptor also results in an arrest of the release of stored excitatory and inhibitory neurotransmitters; 5, decrease in native neurotransmitters reduces binding to postsynaptic receptors; 6, AEA and 2-AG re-enter the post- or presynaptic nerve terminals where they are catabolised by FAAH or MAGL, respectively, to yield either arachidonic acid (AA) and ethanolamine (ETA), or AA and glycerol.