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J Biol Chem, Vol. 274, Issue 17, 12087-12094, April 23, 1999
From the Department of Pharmacology, Temple University School of
Medicine, Philadelphia, Pennsylvania 19140 and the
Agonist-promoted internalization of some G
protein-coupled receptors has been shown to mediate receptor
desensitization, resensitization, and down-regulation. In this study,
we investigated whether opioids induced internalization of the human
and rat
U50,488H-induced Internalization of the Human
Opioid Receptor
Involves a 
-Arrestin- and Dynamin-dependent
Mechanism
RECEPTOR INTERNALIZATION IS NOT REQUIRED FOR
MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION
,, and Department of Microbiology and Immunology, Kimmel Cancer
Institute, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
opioid receptors stably expressed in Chinese hamster ovary
cells, the potential mechanisms involved in this process and its
possible role in activation of mitogen-activated protein (MAP) kinase.
Exposure of the human receptor to the agonists U50,488H, U69,593,
ethylketocyclazocine, or tifluadom, but not etorphine, promoted
receptor internalization. However, none of these agonists induced
significant internalization of the rat opioid receptor.
U50,488H-induced human receptor internalization was time- and
concentration-dependent, with 30-40% of the receptors
internalized following a 30-min exposure to 1 µM
U50,488H. Agonist removal resulted in the receptors gradually returning
to the cell surface over a 60-min period. The antagonist naloxone
blocked U50,488H-induced internalization without affecting internalization itself, while pretreatment with pertussis toxin had no
effect on U50,488H-induced internalization. In contrast, incubation
with sucrose (0.4-0.8 M) significantly reduced
U50,488H-induced internalization of the receptor. While
co-expression of the wild type GRK2, 
-arrestin, or dynamin I had no
effect on receptor internalization, co-expression of the dominant
negative mutants GRK2-K220R, -arrestin (319-418), or dynamin I-K44A
significantly inhibited receptor internalization. Whether receptor
internalization is critical for MAP kinase activation was next
investigated. Co-expression of dominant negative mutants of
-arrestin or dynamin I, which greatly reduced U50,488H-induced
internalization, did not affect MAP kinase activation by the agonist.
In addition, etorphine, which did not promote human receptor
internalization, was able to fully activate MAP kinase. Moreover,
U50,488H or etorphine stimulation of the rat receptor, which did
not undergo internalization, also effectively activated MAP kinase.
Thus, U50,488H-induced internalization of the human opioid receptor
in Chinese hamster ovary cells occurs via a GRK-, -arrestin-, and
dynamin I-dependent process that likely involves
clathrin-coated pits. In addition, internalization of the receptor
is not required for activation of MAP kinase.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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