RT Journal Article
SR Electronic
T1 Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 884
OP 888
VO 287
IS 3
A1 Bonhaus, D. W.
A1 Chang, L. K.
A1 Kwan, J.
A1 Martin, G. R.
YR 1998
UL http://jpet.aspetjournals.org/content/287/3/884.abstract
AB Cannabinoid receptors couple to both Gs and Giproteins 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 ∼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. The American Society for Pharmacology and Experimental Therapeutics