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J Biol Chem, Vol. 274, Issue 14, 9207-9215, April 2, 1999
From the Department of Pharmacology, University of Minnesota,
Medical School, Minneapolis, Minnesota 55455
Chronic activation of the µ-opioid
receptor (MOR1TAG) results in the loss of agonist response that
has been attributed to desensitization and down-regulation of the
receptor. It has been suggested that opioid receptor phosphorylation is
the mechanism by which this desensitization and down-regulation occurs.
When MOR1TAG was stably expressed in both neuroblastoma neuro2A and human embryonic kidney HEK293 cells, the opioid agonist
[D-Ala2,MePhe4,Gly5-ol]enkephalin
(DAMGO) induced a time- and concentration-dependent phosphorylation of the receptor, in both cell lines, that could be
reversed by the antagonist naloxone. Protein kinase C can phosphorylate the receptor, but is not involved in DAMGO-induced MOR1TAG
phosphorylation. The rapid rate of receptor phosphorylation, occurring
within minutes, did not correlate with the rate of the loss of
agonist-mediated inhibition of adenylyl cyclase, which occurs in hours.
This lack of correlation between receptor phosphorylation and the loss
of response was further demonstrated when receptor phosphorylation was
increased by either calyculin A or overexpression of the G-protein receptor kinases. Calyculin A increased the magnitude of MOR1TAG phosphorylation without altering the DAMGO-induced loss of the adenylyl
cyclase response. Similarly, when µ- and 
-opioid (DOR1TAG) receptors were expressed in the same system, overexpression of 
-adrenergic receptor kinase 2 elevated agonist-induced
phosphorylation for both receptors. However, in the same cell lines
under the same conditions, overexpression of -adrenergic receptor
kinase 2 and -arrestin 2 accelerated the rate of DPDPE- but not
DAMGO-induced receptor desensitization. Thus, these data show that
phosphorylation of MOR1TAG is not an obligatory event for the
DAMGO-induced loss in the adenylyl cyclase regulation by the receptor.
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