title: Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1.
abstract: The endothelium-dependent mesenteric vasorelaxant effect of anandamide has been attributed to stimulation of a Gi/Go-coupled receptor, for which the nonpsychoactive analog abnormal cannabidiol (abn-cbd, (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)olivetol) is a selective agonist and the compound O-1918 ((-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol) is a selective antagonist. In human umbilical vein endothelial cells abn-cbd was reported to increase the phosphorylation of p44/42 mitogen activated protein kinase (MAPK) and protein kinase B/Akt, and these effects could be inhibited by pertussis toxin, by phosphatidylinositol 3-kinase (PI3K) inhibitors or by O-1918 [Mol. Pharmacol. 63 (2003) 699]. In the present experiments, abn-cbd caused a concentration-dependent increase in human umbilical vein endothelial cell migration, as quantified in a transwell chamber. This effect was antagonized by O-1918, by the PI3K inhibitor wortmannin, and by pertussis toxin, but not by the cannabinoid CB1 receptor antagonist AM251 or the cannabinoid CB2 receptor antagonist SR144528. The EDG-1 receptor agonist sphingosine-1-phosphate also increased human umbilical vein endothelial cell migration, but this response was unaffected by O-1918. In Chinese hamster ovary cells stably transfected with the gene encoding the EDG-1 receptor, p44/42 MAPK phosphorylation was unaffected by abn-cbd, but strongly induced by sphingosine-1-phosphate. These results indicate that an abn-cbd-sensitive endothelial receptor distinct from cannabinoid CB1, CB2 or EDG-1 receptors mediates not only vasorelaxation but also endothelial cell migration.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-8115, USA.
authors.forename: Fong Ming
authors.initials: FM
authors.lastname: Mo
authors.forename: László
authors.initials: L
authors.lastname: Offertáler
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002185:Cannabidiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D042783:Endothelial Cells / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D008246:Lysophospholipids / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D049349:Receptors, Lysosphingolipid; D012118:Resorcinols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D014471:Umbilical Veins / Q000166:cytology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008246:Lysophospholipids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; D012118:Resorcinols; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C485529:cannabidiol (abn-cbd, (-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)olivetol); D002185:Cannabidiol; C060506:sphingosine 1-phosphate; D037342:Pertussis Toxin; D019950:Mitogen-Activated Protein Kinase 1; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine; D000077191:Wortmannin