The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt.
Cannabinoids exert most of their effects in the central nervous system through the CB(1) cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin and wortmannin blocked the CB(1) receptor-evoked activation of PKB, pointing to the sequential involvement of a G(i)/G(o) protein and phosphoinositide 3'-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB(1) receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB(2) receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB(1) receptor.
Gómez del Pulgar
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Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain.
Velasco
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Guzmán
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D037361:Adenylate Cyclase Toxin; D000730:Androstadienes / Q000494:pharmacology; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001254:Astrocytoma; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D063388:Endocannabinoids; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D018922:HL-60 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000077191:Wortmannin
D037361:Adenylate Cyclase Toxin; D000730:Androstadienes; D001095:Arachidonic Acids; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002186:Cannabinoids; D013759:Dronabinol; D063388:Endocannabinoids; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D020962:Heterotrimeric GTP-Binding Proteins; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053284:Polyunsaturated Alkamides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D010566:Virulence Factors, Bordetella; D000077191:Wortmannin; C494918:AKT1 protein, human; C078814:anandamide