A biosynthetic pathway for anandamide.
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.
Liu
Jie
J
Laboratories of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. jiel@mail.nih.gov
Wang
Lei
L
Harvey-White
Judith
J
Osei-Hyiaman
Douglas
D
Razdan
Raj
R
Gong
Qian
Q
Chan
Andrew C
AC
Zhou
Zhifeng
Z
Huang
Bill X
BX
Kim
Hee-Yong
HY
Kunos
George
G
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis*; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000096:biosynthesis*; D002460:Cell Line; D018076:DNA, Complementary; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010957:Plasmids; D053284:Polyunsaturated Alkamides; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D001095:Arachidonic Acids; D002186:Cannabinoids; D018076:DNA, Complementary; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C109143:N-arachidonylphosphatidylethanolamine; D010714:Phosphatidylethanolamines; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases; C516766:Ptpn22 protein, mouse; D010738:Type C Phospholipases; C078814:anandamide