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. Author manuscript; available in PMC: 2016 Oct 1.
Published in final edited form as: Nat Rev Neurosci. 2015 Sep 16;16(10):579–594. doi: 10.1038/nrn4004

Figure 1. Endocannabinoid biosynthesis, signaling and clearance.

Figure 1

The most commonly accepted route for AEA synthesis is from catalysis of N-arachidonoyl-phosphatidylethanolamine (NAPE) via a specific phospholipase D (NAPE-PLD). 2-AG derives from the hydrolysis of 1,2-diacylglycerol (DAG) via the sn-1-selective DAG lipases DAGLα and DAGLβ. DAGLα is found on the plasma membranes of both dopaminergic and non-dopaminergic neurons in the VTA, opposite CB1R-expressing glutamate and GABA axon terminals200. Termination of EC signaling is initiated by cellular reuptake followed by enzyme-mediated hydrolytic cleavage. 2-AG hydrolysis is primarily mediated by presynaptic monoacylglycerol lipase (MAGL), though post-synaptic enzymes including ABHD6 also contribute to 2-AG clearance. AEA hydrolysis occurs in postsynaptic cells through fatty acid amide hydrolase (FAAH). Although these mechanisms are depicted here in the VTA, the pre- and post-synaptic organization of EC biosynthetic and hydrolytic enzymes is generally conserved throughout the brain.