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 alpha(2)-adrenergic rec
eptor (AR) transfectants, the alpha(2)-AR agonists clonidine, oxymetazoline
, UK-14304, and epinephrine increased [S-35]guanosine-5'-O-(3-thio)triphosp
hate binding in a dose-dependent manner from a basal Value of 101.2 +/- 6.5
fmol/mg to a maximal response (100 mu M) of 196.6 +/- 9.8, 182.3 +/- 2, 32
8.1 +/- 11.2, and 340.6 +/- 3 fmol/mg, respectively. Thus, clonidine and ox
ymetazoline behaved as-partial agonists. Receptor-mediated activation of G
proteins in membrane preparations was blocked by cell pretreatment with per
tussis toxin, indicating receptor coupling to the subgroup of pertussis tox
in-sensitive G protein (Gi alpha 2,3) expressed in NIH-3T3 cells. Ectopic e
xpression of Goal but not Gi alpha 1 increased the relative efficacy of clo
nidine and oxymetazoline such that the two ligands now behaved as close to
full agonists in this assay system. The relationship between full and parti
al agonists in the different genetic backgrounds was. not altered by progre
ssive reduction in the amount of G protein: available for coupling to recep
tor. The increased efficacy observed for clonidine in the Goal transfectant
s was not due;:to changes in the relative affinities or amounts of high-aff
inity, Gpp(NH)p-sensitive binding of agonist. These data suggest that there
is little difference in the ability of clonidine to interact with or stabi
lize alpha(2)-AR-Gi alpha 2/Gi alpha 3 versus alpha(2)-AR-Go alpha 1 comple
xes, but that the subsequent step of signal transfer from receptor to G pro
tein is more readily achieved for the clonidine/alpha(2)-AR/Go alpha 1 comp
lex. Such observations have important implications for receptor theory and
drug development.