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Vol. 58, Issue 4, 795-801, October 2000
-Opioid Receptor: Internalization Is Required for Down-Regulation
Department of Pharmacology, Temple University School of Medicine,
Philadelphia, Pennsylvania (J.-G.L., L.-Y.L.-C.); and Department of
Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson
University, Philadelphia, Pennsylvania (J.L.B.)
Previously, we showed that the human 
-opioid receptor (hkor) stably
expressed in Chinese hamster ovary (CHO) cells underwent down-regulation after prolonged U50,488H treatment. In the present study, we determined the mechanisms underlying this process. U50,488H caused a significant down-regulation of the hkor, although etorphine did not. Neither U50,488H nor etorphine caused down-regulation of the
rat -opioid receptor. Thus, similar to internalization, there are
agonist and species differences in down-regulation of -opioid
receptors. Expression of the dominant negative mutants arrestin-2(319-418) or dynamin I-K44A significantly reduced
U50,488H-induced down-regulation of the hkor. Coexpression of GRK2 or
GRK2 and arrestin-2 permitted etorphine to induce down-regulation of
the hkor, although expression of arrestin-2 or dynamin I alone did not.
Expression of the dominant negative mutants rab5A-N133I or rab7-N125I
blunted U50,488H-induced down-regulation. Pretreatment with lysosomal
enzyme inhibitors
[(2S,3S)trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester or chloroquine] or proteasome inhibitors (proteasome inhibitor I, MG-132, or lactacystin) decreased the extent of
U50,488H-induced down-regulation. A combination of chloroquine and
proteasome inhibitor I abolished U50,488H-induced down-regulation.
These results indicate that U50,488H-induced down-regulation of the
hkor involves GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent
mechanisms and receptors seem to be trafficked to lysosomes and
proteasomes for degradation. Thus, U50,488H-induced internalization and
down-regulation of the hkor share initial common mechanisms. To the
best of our knowledge, these results represent the first report on the
involvement of both rab5 and rab7 in agonist-induced down-regulation of
a G protein-coupled receptor. In addition, this study is among the first to show the involvement of proteasomes in agonist-induced down-regulation of a G protein-coupled receptor.
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