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Vol. 55, Issue 3, 473-480, March 1999
Sanofi Recherche, Montpellier cedex 04, France
The peripheral cannabinoid receptor (CB2) is a G protein-coupled
receptor that is both positively and negatively coupled to the
mitogen-activated protein kinase (MAPK) and cAMP pathways, respectively, through a Bordetella pertussis toxin-sensitive G protein. CB2 receptor-transfected Chinese hamster ovary cells exhibit
high constitutive activity blocked by the CB2-selective ligand, SR
144528, working as an inverse agonist. We showed here that in addition
to the inhibition of autoactivated CB2 in this model, we found that SR
144528 inhibited the MAPK activation induced by
Gi-dependent receptors such as receptor-tyrosine kinase
(insulin, insulin-like growth factor 1) or G protein-coupled receptors
(lysophosphatidic acid), but not by Gi-independent
receptors such as the fibroblast growth factor receptor. We showed that
this SR 144528 inhibitory effect on Gi-dependent receptors
was mediated by a direct Gi protein inhibition
through CB2 receptors. Indeed, we found that through binding to the CB2
receptors, SR 144528 blocked the direct activation of the
Gi protein by mastoparan analog in Chinese hamster ovary CB2 cell membranes. Furthermore, we described that sustained treatment with SR 144528 induced an up-regulation of the cellular Gi
protein level as shown in Western blotting as well as in confocal
microscopic experiments. This up-regulation occurred with a concomitant
loss of SR 144528 ability to inhibit the insulin or lysophosphatidic acid-induced MAPK activation. This inverse agonist-induced modulation of the Gi strongly suggests that the modulated protein is
functionally associated with the complex SR 144528/CB2 receptors, and
that the Gi level may account for the heterologous
desensitization phenomena.
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