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Vol. 287, Issue 3, 884-888, December 1998
Department of Molecular Pharmacology, Center for Biological
Research, Neurobiology Unit, Roche Bioscience, Palo Alto, California
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 ~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.
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