A biosynthetic pathway for anandamide

• DOI: 10.1073/pnas.0601832103
• Publication Date: 2006-08-28T22:10:40Z
• Authors: Jie Liu; Lei Wang; Judith Harvey-White; Douglas Osei-Hyiaman; Raj Razdan; Qian Gong; Andrew C. Chan; Zhifeng Zhou; Bill X. Huang; Hee-Yong Kim; George Kunos
• Keywords: Lipopolysaccharides; Mice, Knockout; 0301 basic medicine; DNA, Complementary; Cannabinoids; Polyunsaturated Alkamides; Macrophages; Phosphatidylethanolamines; Brain; Protein Tyrosine Phosphatase, Non-Receptor Type 22; Arachidonic Acids; In Vitro Techniques; Immunohistochemistry; Cell Line; Kinetics; Mice; 03 medical and health sciences; Animals; Enzyme Inhibitors; Protein Tyrosine Phosphatases; Endocannabinoids; Plasmids

The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released “on demand” by neurons in the brain. Anandamide is also generated by macrophages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N -arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE–PLD). Here we document a biosynthetic pathway for anandamide in mouse brain and RAW264.7 macrophages that involves the phospholipase C (PLC)-catalyzed cleavage of NAPE to generate a lipid, phosphoanandamide, which is subsequently dephosphorylated by phosphatases, including PTPN22, previously described as a protein tyrosine phosphatase. Bacterial endotoxin (LPS)-induced synthesis of anandamide in macrophages is mediated exclusively by the PLC/phosphatase pathway, which is up-regulated by LPS, whereas NAPE–PLD is down-regulated by LPS and functions as a salvage pathway of anandamide synthesis when the PLC/phosphatase pathway is compromised. Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC/phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target.