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Vol. 287, Issue 3, 1038-1047, December 1998
Sanofi Recherche, 371 rue du Professeur J. Blayac, 34184 Montpellier CEDEX 04, France
We have investigated the adaptive changes of the human central
cannabinoid receptor (CB1) stably expressed in Chinese hamster ovary
cells (CHO-CB1), after agonist (CP 55,940) or selective CB1 inverse
agonist (SR 141716) treatment. CB1 receptor density and affinity
constant as measured by binding assays with both tritiated ligands
remained essentially unchanged after varying period exposure of CHO-CB1
cells (from 30 min to 72 hr) to saturating concentrations of CP 55,940 or SR 141716. However, using a C-myc-tagged version of the CB1
receptor, FACS analysis and confocal microscopy studies on CB1
expression indicated that the agonist promoted a disappearance of cell
surface receptor although inverse agonist increased its cell surface
density. Taken together these results suggest that 1) agonist induces
internalization of the receptor into a cellular compartment that would
be still accessible to both the hydrophobic ligands CP 55,940 or SR
141716; 2) inverse-agonist promotes externalization of the receptor
from an intracellular preexisting pool to the cell surface. In
parallel, we also investigated the associated effects of CP 55,940 and
SR 141716 on CB1 receptor-coupled second messengers. We showed that
preexposure of cells to CP 55,940 induced a rapid desensitization of
the CB1 to the agonist response. The ability of CP 55,940 to inhibit
the forskolin-stimulated adenylyl cyclase and to activate the
mitogen-activated protein kinase activity was dramatically reduced. By
striking contrast, SR 141716 pretreatment of CHO-CB1 cells not only had
no significant effect on the potency of CP 55,940 to inhibit the
forskolin-stimulated adenylyl cyclase but also induced a significant
enhancement of the CP 55,940 ability to stimulate the mitogen-activated
protein kinase activity. These results suggest that the modulation of
the number of cell surface receptor could lead to functional
desensitization or sensitization of the CB1 receptors.
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