Abstract
The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Aorta / cytology
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Aorta / drug effects
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Arachidonic Acids / chemistry*
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Arachidonic Acids / isolation & purification
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Arachidonic Acids / pharmacology*
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Cannabinoid Receptor Agonists*
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Cattle
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Cells, Cultured
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / enzymology
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Mesenteric Arteries / cytology
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Mesenteric Arteries / drug effects
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Mice
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 3 / drug effects
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Phosphorylation
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Proto-Oncogene Proteins c-akt / drug effects
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Rats
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / metabolism
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Serine / analogs & derivatives*
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Serine / chemistry
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Serine / isolation & purification
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Serine / pharmacology
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TRPV Cation Channels / metabolism
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Vasodilator Agents / chemistry*
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Vasodilator Agents / isolation & purification
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Vasodilator Agents / pharmacology*
Substances
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Arachidonic Acids
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Cannabinoid Receptor Agonists
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N-arachidonoyl L-serine
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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TRPV Cation Channels
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TRPV1 receptor
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Vasodilator Agents
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Serine
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3