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-Opioid Receptor: Requirement of a High Affinity Receptor/G Protein
Complex Formation
Department of Pharmacology, University of Minnesota, Medical
School, Minneapolis, Minnesota 55455
Chronic opioid treatment of Neuro2A cells stably expressing
either 
-opioid receptor (DOR) or µ-opioid receptor (MOR) resulted in agonist-dependent receptor down-regulation. Although there is high
homology in the DOR and MOR amino acid sequences, there is an apparent
difference in the regulation of the cellular levels of these two
receptors. The ability of 24-hr
[D-Pen2,D-Pen5]enkephalin
(DPDPE) treatment to internalize and down-regulate DORs expressed in
Neuro2A remained intact after pertussis toxin (PTX)
pretreatment, which uncouples the receptor from G proteins. In
contrast, the ability of
[D-Ala2,N-MePhe4,Gly-ol5]enkephalin
(DAMGO) to internalize and down-regulate MORs in Neuro2A cells was completely abolished by PTX pretreatment. The requirement of
functional MOR but not DOR in agonist-induced receptor down-regulation was further demonstrated by site-directed mutagenesis of the receptors. When Asp114 in transmembrane 2 of MOR was converted to alanine, the
ability was abolished of DAMGO or morphine to inhibit
forskolin-stimulated [3H]cAMP production in
Neuro2A cells stably expressing this mutant receptor. There
was a parallel decrease in agonist affinity and elimination of the
agonist-induced receptor down-regulation. On the other hand, although
the equivalent mutation of Asp95 to alanine in DOR likewise resulted in
the inability of DPDPE to inhibit [3H]cAMP production,
the ability of DPDPE to down-regulate this mutant receptor after 24-hr
treatment was unaffected. This difference in MOR and DOR
down-regulation could be caused by the differences in the ability of
these two receptors to form high affinity complexes with G proteins.
DOR retained the ability to form high affinity complexes even after PTX
pretreatment or after mutation of Asp95 in transmembrane 2. In
contrast, MOR existed only in the low affinity, uncoupled state after
PTX pretreatment or after conversion of Asp114 to alanine. Therefore,
in Neuro2A cells, agonist-induced opioid receptor
down-regulation seems to depend directly on the formation of the high
affinity receptor complexes and not on the activation of the receptors
and subsequent transduction of the signals.
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