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J Biol Chem, Vol. 274, Issue 41, 28900-28908, October 8, 1999

₂-Adrenergic Receptor Down-regulation
EVIDENCE FOR A PATHWAY THAT DOES NOT REQUIRE ENDOCYTOSIS

Ralf Jockers, Stéphane Angers^¶, Angelo Da Silva^¶, Philippe Benaroch, A. Donny Strosberg, Michel Bouvier^¶, and Stefano Marullo^**

From the  Immuno-Pharmacologie Moléculaire, UPR 415 of CNRS and University of Paris VII, ICGM, 75014 Paris, France, ^** Pharmacologie Cellulaire et Moléculaire, UPRES-A 8068 of CNRS and University of Paris V, ICGM, Pavillon Gustave Roussy, 75679 Paris CEDEX 14, France, and ^¶ Département de Biochimie, Université de Montréal, Montréal H3C 3J7, Canada

Sustained activation of most G protein-coupled receptors causes a time-dependent reduction of receptor density in intact cells. This phenomenon, known as down-regulation, is believed to depend on a ligand-promoted change of receptor sorting from the default endosome-plasma membrane recycling pathway to the endosome-lysosome degradation pathway. This model is based on previous studies of epidermal growth factor (EGF) receptor degradation and implies that receptors need to be endocytosed to be down-regulated.

In stable clones of L cells expressing ₂-adrenergic receptors (₂ARs), sustained agonist treatment caused a time-dependant decrease in both ₂AR binding sites and immuno-detectable receptor. Blocking ₂AR endocytosis with chemical treatments or by expressing a dominant negative mutant of dynamin could not prevent this phenomenon. Specific blockers of the two main intracellular degradation pathways, lysosomal and proteasome-associated, were ineffective in preventing ₂AR down-regulation. Further evidence for an endocytosis-independent pathway of ₂AR down-regulation was provided by studies in A431 cells, a cell line expressing both endogenous ₂AR and EGF receptors. In these cells, inhibition of endocytosis and inactivation of the lysosomal degradation pathway did not block ₂AR down-regulation, whereas EGF degradation was inhibited. These data indicate that, contrary to what is currently postulated, receptor endocytosis is not a necessary prerequisite for ₂AR down-regulation and that the inactivation of ₂ARs, leading to a reduction in binding sites, may occur at the plasma membrane.

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