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Vol. 56, Issue 3, 651-656, September 1999
Department of Pharmacology, Medical University of South Carolina,
Charleston, South Carolina
An agonist at a specific G protein-coupled receptor may exhibit
a range of efficacies for any given response in a cell-specific manner.
We report that the relationship between different states of agonism is
regulated by the type of G protein expressed in the cell. In NIH-3T3
2-adrenergic receptor (AR) transfectants, the
2-AR agonists clonidine, oxymetazoline, UK-14304, and
epinephrine increased
[35S]guanosine-5'-O-(3-thio)triphosphate
binding in a dose-dependent manner from a basal value of 101.2 ± 6.5 fmol/mg to a maximal response (100 µM) of 196.6 ± 9.8, 182.3 ± 2, 328.1 ± 11.2, and 340.6 ± 3 fmol/mg,
respectively. Thus, clonidine and oxymetazoline behaved as partial
agonists. Receptor-mediated activation of G proteins in membrane
preparations was blocked by cell pretreatment with pertussis toxin,
indicating receptor coupling to the subgroup of pertussis
toxin-sensitive G protein (Gi2,3) expressed in NIH-3T3 cells.
Ectopic expression of Go1 but not Gi1 increased the relative efficacy of clonidine and oxymetazoline such that the two ligands now
behaved as close to full agonists in this assay system. The relationship between full and partial agonists in the different genetic
backgrounds was not altered by progressive reduction in the amount of G
protein available for coupling to receptor. The increased efficacy
observed for clonidine in the Go1 transfectants was not due to
changes in the relative affinities or amounts of high-affinity,
Gpp(NH)p-sensitive binding of agonist. These data suggest that there is
little difference in the ability of clonidine to interact with or
stabilize 2-AR-Gi2/Gi3 versus
2-AR-Go1 complexes, but that the subsequent step of
signal transfer from receptor to G protein is more readily achieved for
the clonidine/2-AR/Go1 complex. Such observations
have important implications for receptor theory and drug development.
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