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Molecular Neuropharmacology Section, Departments of Psychiatry and
Pharmacology, and Vermont Cancer Center, University of Vermont,
Burlington, Vermont 05405 (E.S.B., T.A.S., M.R.B.) and
Receptor
Technologies, Inc., Winooski, Vermont 05404 (E.S.B., M.R.B.)
We have examined the effects of raising G protein concentration on the
pharmacology of a series of agonist and antagonist ligands at the m1,
m3, and m5 muscarinic subtypes using a functional assay. Overexpression
of G
q induced constitutive activity of these receptors.
The constitutive activity was reversed completely by every muscarinic
antagonist tested, which indicates that they are all negative
antagonists (inverse agonists). The potencies of antagonists for
reversing G protein-induced activity and agonist-induced activity were
identical, suggesting the same mechanism of action. Overexpression of
Gq increased the potencies of every tested agonist and
the efficacies of all partial agonists. The fold-gains in potency were
positively correlated with ligand efficacy with the most efficacious
agonists displaying the greatest potency gains. In addition, the
efficacies of partial agonists approached those of full agonists.
Constitutive activity of receptors has been explained by allosteric
models in which receptors exist in spontaneous equilibrium between
active and inactive conformations that are stabilized by agonists and
antagonists, respectively. In this context, drug efficacy and potency
are interrelated because they both depend on the same parameters,
namely the absolute and relative affinities of a compound for receptors
in active and inactive states and the ratio and concentrations of
receptors in active and inactive states. All of our data are consistent with this model, in which raising G protein levels favors formation of
the active conformation of receptors. Based on our findings, regulation
of G protein concentration may be an important means of controlling
receptor activity in vivo. These results define the functional
relationship between G protein levels and muscarinic receptor
pharmacology.
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