title: Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses.
abstract: Cannabinoid receptors couple to both Gs and Gi proteins and can consequently stimulate or inhibit the formation of cAMP. To test whether there is specificity among cannabinoid receptor agonists in activating Gs- or Gi-coupled pathways, the potency and intrinsic activity of various cannabinoid receptor ligands in stimulating or inhibiting cAMP accumulation were quantified. The rank order of potencies of cannabinoid receptor agonists in increasing or inhibiting forskolin-stimulated cAMP accumulation, in CHO cells expressing hCB1 receptors, was identical (HU-210 > CP-55,940 > THC > WIN-55212-2 > anandamide). However, the activities of these agonists were different in the two assays with anandamide and CP-55,940 being markedly less efficacious in stimulating the accumulation of cAMP than in inhibiting its formation. Studies examining the effects of forskolin on cannabinoid receptor mediated stimulation of adenyly cyclase also revealed differences among agonists in as much as forskolin enhanced the potency of HU-210 and CP-55,940 by approximately 100-fold but, by contrast, had no effect on the potency of WIN-55212-2 or anandamide. Taken together these findings demonstrate marked differences among cannabinoid receptor agonists in their activation of intracellular transduction pathways. This provides support for the emerging concept of agonist-specific trafficking of cellular responses and further suggests strategies for developing receptor agonists with increased therapeutic utility.
authors.affiliation: Department of Molecular Pharmacology, Center for Biological Research, Neurobiology Unit, Roche Bioscience, Palo Alto, California, USA.Doug.Bonhaus@roche.com
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: L K
authors.initials: LK
authors.lastname: Chang
authors.forename: J
authors.initials: J
authors.lastname: Kwan
authors.forename: G R
authors.initials: GR
authors.lastname: Martin
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D016466:CHO Cells; D005576:Colforsin; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D063388:Endocannabinoids; D004789:Enzyme Activation; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D001095:Arachidonic Acids; D048588:Benzoxazines; D003511:Cyclohexanols; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005576:Colforsin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C062018:HU 211; C078814:anandamide