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-O-(
-thio)-triphosphate Binding in Rat
Thalamus and Cultured Cell Lines: Signal Transduction Mechanisms
Underlying Agonist Efficacy
Department of Physiology and Pharmacology, Bowman Gray School of
Medicine, Wake Forest University, Winston-Salem, North Carolina 27157
G protein activation by different µ-selective opioid agonists was
examined in rat thalamus, SK-N-SH cells, and µ-opioid
receptor-transfected mMOR-CHO cells using agonist-stimulated
guanosine-5
-O-(
-thio)-triphosphate ([35S]GTPS) binding to membranes in the presence of
excess GDP.
[D-Ala2,N-MePhe4,Gly5-ol]Enkephalin
(DAMGO) was the most efficacious agonist in rat thalamus and SK-N-SH
cells, followed by (in rank order) fentanyl = morphine 
buprenorphine. In mMOR-CHO cells expressing a high density of µ receptors, no differences were observed among DAMGO, morphine or
fentanyl, but these agonists were more efficacious than buprenorphine,
which was more efficacious than levallorphan. In all three systems,
efficacy differences were magnified by increasing GDP concentrations,
indicating that the activity state of G proteins can affect agonist
efficacy. Scatchard analysis of net agonist-stimulated [35S]GTPS binding revealed two major components
responsible for agonist efficacy differences. First, differences in the
KD values of agonist-stimulated
[35S]GTPS binding between high efficacy agonists
(DAMGO, fentanyl, and morphine) and classic partial agonists
(buprenorphine and levallorphan) were observed in all three systems.
Second, differences in the Bmax value of
agonist-stimulated [35S]GTPS binding were observed
between DAMGO and morphine or fentanyl in rat thalamus and SK-N-SH
cells and between the high efficacy agonists and buprenorphine or
levallorphan in all three systems. These results suggest that
µ-opioid agonist efficacy is determined by the magnitude of the
receptor-mediated affinity shift in the binding of GTP (or
[35S]GTPS) versus GDP to the G protein and by the
number of G proteins activated per occupied receptor.
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