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Vol. 54, Issue 4, 704-711, October 1998
Department of Pharmacology, University of Washington, Seattle,
Washington 98195-7280
Using Xenopus laevis oocytes coexpressing mammalian
µ-opioid receptors (MORs), 
-adrenergic receptor kinase 2 (-ARK2) [also called G protein-coupled receptor kinase (GRK3)],
and -arrestin 2 (-arr 2), we compared the rates of -ARK2
(GRK3)- and -arr 2-mediated homologous receptor desensitization
produced by treatment with opioid agonists of different efficacies. The
response to MOR activation was measured using two-electrode voltage
clamp as an increase in the conductance of the coexpressed G
protein-coupled inwardly rectifying potassium (heteromultimer of
KIR3.1 and KIR3.4) channels. Treatment with
opioids of high efficacy, either
[D-Ala2,N-MePhe4,Gly-ol5]-enkephalin,
fentanyl, or sufentanyl, produced a GRK3- and -arr 2-dependent
reduction in response in <20 min, whereas treatment with the partial
agonist morphine produced receptor desensitization at a significantly
slower rate. Because GRK3 requires activation and membrane targeting by
free G protein 
subunits released after agonist-mediated
activation of G proteins, a low efficacy agonist such as morphine may
produce weak receptor desensitization as a consequence of poor GRK3
activation. To address this hypothesis, we substituted GRK5, a GRK that
does not require activation by G protein . In oocytes expressing
GRK5 instead of GRK3, both [D-Ala2,N-MePhe4,Gly-ol5]enkephalin
and fentanyl, but not morphine, produced desensitization of
MOR-activated potassium conductance. Thus, µ-opioid agonists produced
significant receptor desensitization, mediated by either GRK3 or GRK5,
at a rate dependent on agonist efficacy.
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