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Vol. 52, Issue 6, 1087-1094, 1997
Department of Biochemistry and Biophysics (W.K.V., D.M.S., M.I.S.)
and
Environmental Health Sciences Center (M.I.S.), Oregon State
University, Corvallis, Oregon 97331-7305
The first step in the transmembrane signal mediated by G
protein-coupled receptors is binding of agonist to receptors at the cell surface. The mechanism of the resulting receptor activation is not
clear, but models based on the ternary complex model are capable of
explaining most of the observations that have been reported in G
protein-coupled receptors. This model suggests that a single
agonist/receptor/G protein complex capable of activating G protein is
formed as the result of agonist binding. Extensions of this basic model
differ primarily in whether an equilibrium between active and inactive
conformations is required to explain experimental results. We report
results on ligand binding and coupling to physiological effector
systems of the m2 muscarinic acetylcholine receptor site-directed
mutant Y403F (residue 403 mutated from tyrosine to phenylalanine)
expressed in Chinese hamster ovary cells and compare our results with
results reported for the homologous Y506F mutation in the m3 muscarinic
receptor [J. Biol. Chem. 267:19313-19319
(1992)]. The mutation in the m2 muscarinic receptor reduced absolute
agonist affinities more dramatically than in the m3 muscarinic
receptor. Unlike the results reported for the m3 subtype mutant, in
which coupling to physiological effector systems was reduced, coupling
to effector systems for the mutant in the m2 subtype was robust. In the
Y403F m2 muscarinic receptor, the difference between the two agonist
binding affinities was greater than in the wild-type receptor, whereas
in the m3 subtype, the effect of the mutation was to decrease this
difference. A prediction of the ternary complex model is that relative
binding affinities will affect the steady state concentration of the
agonist/receptor/G protein complex and, as the result, the extent of G
protein coupling. These results can best be rationalized by this model,
which suggests that the activation of G protein-coupled receptors is
achieved by the relative affinity of agonist for two receptor states
and does not require the existence of multiple states in conformational equilibrium.
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