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Vol. 297, Issue 3, 1218-1226, June 2001
Howard Hughes Medical Institute (R.S., K.W.-S., U.G., B.K.K.),
Division of Cardiovascular Medicine (B.K.K.), Stanford University
Medical School, Stanford, California
The interaction of an agonist-bound G-protein-coupled receptor (GPCR)
with its cognate G-protein initiates a sequence of experimentally quantifiable changes in both the GPCR and G-protein. These include the
release of GDP from G
, the formation of a ternary
complex between the nucleotide-free G-protein and the GPCR, which has a
high affinity for agonist, followed by the binding of GTP to G, the dissociation of the GPCR/G-protein complex, and
the hydrolysis of GTP. The efficacy of an agonist is a measure of its
ability to activate this cascade. It has been proposed that efficacy
reflects the ability of the agonist to stabilize the active state of
the GPCR. We examined a series of 
2-adrenoceptor (2AR) agonists (weak partial agonists to full agonists)
for their efficacy at promoting two different steps of the G-protein
activation/deactivation cycle: stabilizing the ternary complex
(high-affinity, GTP-sensitive agonist binding), and steady-state GTPase
activity. We obtained results for the wild-type 2AR and
a constitutively active mutant of the 2AR
(2ARCAM) using fusion proteins between the
GPCRs and Gs to facilitate GPCR/G-protein interactions.
There was no correlation between efficacy of ligands in activating
GTPase and their ability to stabilize the ternary complex at
2ARCAM. Our results suggest that the GPCR
state that optimally promotes the GDP release and GTP binding is
different from the GPCR state that stabilizes the ternary complex. By
strongly stabilizing the ternary complex, certain partial agonists may
reduce the rate of G-protein turnover relative to a full agonist.
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