Up-regulation of a constitutively active form of the β2-adrenoceptor by sustained treatment with inverse agonists but not antagonists

AbstractIn neuroblastoma × glioma hybrid, NG108-15, cells transfected to stably express a constitutively active mutant (CAM) form of the human R2-adrenoceptor, the β-adrenoceptor ligands sotalol and betaxolol functioned as inverse agonists as they reduced basal adenylyl cyclase activity whereas the antagonists dihydroalprenolol and propranolol did not. Maintained presence of the CAM β2-adrenoceptor inverse agonists but not the antagonists in the culture medium of the cells resulted in a substantial, concentration-dependent, up-regulation of the CAMβ2-adrenoceptor. Up-regulation of the CAMβ2-adrenoceptor by the inverse agonists was prevented by co-incubation of the cells with either propranolol or dihydroalprenolol. Neither maintained elevation of cAMP levels nor the inhibition of adenylyl cyclase activity altered the ability of the inverse agonist ligands to cause receptor up-regulation