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Research ArticleArticle

Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses

D. W. Bonhaus, L. K. Chang, J. Kwan and G. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 884-888;
D. W. Bonhaus
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L. K. Chang
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J. Kwan
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G. R. Martin
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Abstract

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.

Footnotes

  • Send reprint requests to: Douglas W. Bonhaus, Ph.D., Department of Molecular Pharmacology, Roche Bioscience, Neurobiology Unit, 3401 Hillview Avenue, Building R2–101, Palo Alto, CA 94304. E-mail: Doug.Bonhaus{at}roche.com

  • Abbreviations:
    cAMP
    cyclic AMP
    CB
    cannabinoid
    CP-55
    940, [1α,2β-(R)-5α]-(−)-5 (1,1-dimethylheptyl-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol
    HBSS
    Hanks’ balanced salt solution
    HEPES
    4-(2-hydroxyethyl)-1-piperaineethanesulfonic acid
    HU-210
    (−)-11-hydroxy-Δ8-tetrahydrocannabinol-dimethylheptyl
    SR141617A
    N-(piperidino-1-yl)-5-(4-chlorphenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3–3-carboxamide hydrochloride
    THC
    Δ9-tetrahydrocannabinol
    WIN-55212–2
    R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-napthalenyl)methanone mesylate
    • Received March 30, 1998.
    • Accepted July 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses

D. W. Bonhaus, L. K. Chang, J. Kwan and G. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 884-888;

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Research ArticleArticle

Dual Activation and Inhibition of Adenylyl Cyclase by Cannabinoid Receptor Agonists: Evidence for Agonist-Specific Trafficking of Intracellular Responses

D. W. Bonhaus, L. K. Chang, J. Kwan and G. R. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 884-888;
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