Dual activation and inhibition of adenylyl cyclase by cannabinoid receptoragonists: Evidence for agonist-specific trafficking of intracellular responses

Cannabinoid receptors couple to both G(s) and G(i) proteins and can consequ ently stimulate or inhibit the formation of cAMP. To test whether there is specificity among cannabinoid receptor agonists in activating G(s)- or G(i) -coupled pathways, the potency and intrinsic activity of various cannabinoi d receptor ligands in stimulating or inhibiting cAMP accumulation were quan tified. The rank order of potencies of cannabinoid receptor agonists in inc reasing or inhibiting forskolin-stimulated cAMP accumulation, in CHO cells expressing hCB(1) receptors, was identical (HU-210 > CP-55,940 > THC > WIN- 55212-2 > anandamide). However, the activities of these agonists were diffe rent in the two assays with anandamide and CP-55,940 being markedly less ef ficacious in stimulating the accumulation of cAMP than in inhibiting its fo rmation. Studies examining the effects of forskolin on cannabinoid receptor mediated stimulation of adenyly cyclase also revealed differences among ag onists in as much as forskolin enhanced the potency of HU-210 and CP-55,940 by similar to 100-fold but, by contrast, had no effect on the potency of W IN-55212-2 or anandamide. Taken together these findings demonstrate marked differences among cannabinoid receptor agonists in their activation of intr acellular transduction pathways. This provides support for the emerging con cept of agonist-specific trafficking of cellular responses and further sugg ests strategies for developing receptor agonists with increased therapeutic utility.