TY - JOUR
T1 - N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties
AU - Milman, Garry
AU - Maor, Yehoshua
AU - Abu-Lafi, Saleh
AU - Horowitz, Michal
AU - Gallily, Ruth
AU - Batkai, Sandor
AU - Mo, Fong Ming
AU - Offertaler, Laszlo
AU - Pacher, Pal
AU - Kunos, George
AU - Mechoulam, Raphael
PY - 2006/2/14
Y1 - 2006/2/14
N2 - 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 TWF-α 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.
AB - 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 TWF-α 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.
KW - Abnormal cannabidiol
KW - Anandamide
KW - Cannabinoids
KW - Endothelium
KW - Reactive oxygen intermediates
UR - http://www.scopus.com/inward/record.url?scp=33144473891&partnerID=8YFLogxK
U2 - 10.1073/pnas.0510676103
DO - 10.1073/pnas.0510676103
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C2 - 16467152
AN - SCOPUS:33144473891
SN - 0027-8424
VL - 103
SP - 2428
EP - 2433
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -