A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions

In the present study, we showed that Chinese hamster ovary (CHO) cells transfected with human central cannabinoid receptor (CB1) exhibit high constitutive activity at both levels of mitogen-activated protein kinase (MAPK) and adenylyl cyclase. These activities could be blocked by the CB1-selective l...

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Bibliographic Details
Published in:The Journal of biological chemistry 1997-08, Vol.272 (35), p.22330
Main Authors: Bouaboula, M, Perrachon, S, Milligan, L, Canat, X, Rinaldi-Carmona, M, Portier, M, Barth, F, Calandra, B, Pecceu, F, Lupker, J, Maffrand, J P, Le Fur, G, Casellas, P
Format: Article
Language:English
Subjects:
Adenylate Cyclase Toxin
Animals
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cannabinoids - antagonists & inhibitors
Cannabinoids - metabolism
CHO Cells
Cricetinae
Cyclohexanols - pharmacology
Enzyme Activation
Humans
Insulin - pharmacology
Insulin-Like Growth Factor I - pharmacology
Pertussis Toxin
Piperidines - pharmacology
Pyrazoles - pharmacology
Receptor Protein-Tyrosine Kinases - metabolism
Receptor, IGF Type 1 - metabolism
Receptors, Cannabinoid
Receptors, Drug - antagonists & inhibitors
Receptors, Drug - metabolism
Rimonabant
Signal Transduction
Virulence Factors, Bordetella - pharmacology
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Summary:In the present study, we showed that Chinese hamster ovary (CHO) cells transfected with human central cannabinoid receptor (CB1) exhibit high constitutive activity at both levels of mitogen-activated protein kinase (MAPK) and adenylyl cyclase. These activities could be blocked by the CB1-selective ligand, SR 141716A, that functions as an inverse agonist. Moreover, binding studies showed that guanine nucleotides decreased the binding of the agonist CP-55,940, an effect usually observed with agonists, whereas it enhanced the binding of SR 141716A, a property of inverse agonists. Unexpectedly, we found that CB1-mediated effects of SR 141716A included inhibition of MAPK activation by pertussis toxin-sensitive receptor-tyrosine kinase such as insulin or insulin-like growth factor 1 receptors but not by pertussis toxin-insensitive receptor-tyrosine kinase such as the fibroblast growth factor receptor. We also observed similar results when cells were stimulated with Mas-7, a mastoparan analog, that directly activates the Gi protein. Furthermore, SR 141716A inhibited guanosine 5'-0-(thiotriphosphate) uptake induced by CP-55,940 or Mas-7 in CHO-CB1 cell membranes. This indicates that, in addition to the inhibition of autoactivated CB1, SR 141716A can deliver a biological signal that blocks the Gi protein and consequently abrogates most of the Gi-mediated responses. By contrast, SR 141716A had no effect on MAPK activation by insulin or IGF1 in CHO cells lacking CB1 receptors, ruling out the possibility of a direct interaction of SR 141716A with the Gi protein. This supports the notion that the Gi protein may act as a negative intracellular signaling cross-talk molecule. From these original results, which considerably enlarge the biological properties of the inverse agonist, we propose a novel model for receptor/ligand interactions.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.35.22330