Cannabinoids Biology: The Search for New Therapeutic Targets

The Endocannabinoid Synapse NAPE (N-arachidonoylphosphatidyl ethanolamine) is hydrolyzed by NAPE phospholipase D (NAPE-PLD) to release free anandamide (AEA). Alternatively, precursor phospholipids are hydrolyzed by diglyceride lipase and phospholipase C to release the resident fatty acid (FA) from the sn-1 position and phosphatidyl-ethanolamine (p-EA) from the sn-3 position, respectively, yielding 2-arachidonoylglycerol (2-AG). Anandamide and 2-AG are agonists at the CB₁ receptor. Anandamide can also be released from postsynaptic terminals to signal in a retrograde fashion to presynaptic CB₁ receptors. The CB₁ receptor either blocks or stimulates adenylate cyclase (AC) depending on cell type. CB₁ receptors block neurotransmitter release from the presynaptic terminal. Disposal of anandamide, to yield EA and arachadonic acid (AA), and 2-AG is via movement across the plasma membrane followed by hydrolysis by cytoplasmic fatty acid amide hydrolase (FAAH). As discussed in the text, this movement of anandamide may involve a protein transporter (blue cylinder) that may work in conjunction with FAAH. 2-AG is also transported across the plasma membrane by a similar process and hydrolyzed by monoacylglyceride lipase.