Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1.
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.
Mo
Fong Ming
FM
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-8115, USA.
Offertáler
László
L
Kunos
George
G
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
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