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Vol. 58, Issue 1, 136-144, July 2000
Centre National de la Recherche Scientifique Unité Propre de
Recherche, Centre National de la Recherche Scientifique-Institut
National de la Santé et de la Recherche Médicale de
Pharmacologie-Endocrinologie, Montpellier, France (S.C., M.S., C.B.,
J.B., A.D.); and Center for Biological Research, Neurobiology Unit,
Roche Bioscience, Palo Alto, California (R.M.E., R.D.C.)
We studied the pharmacological properties of twenty-four
5-hydroxytryptamine (5-HT)4 receptor ligands known to act
as antagonists on 5-HT4 receptors positively coupled to
adenylyl cyclase endogenously expressed in mouse colliculi neurons. In
COS-7 cells expressing human or mouse 5-HT4(a) receptors
(100-8000 fmol/mg of protein), we found neutral antagonists, partial
agonists, and inverse agonists. The majority of neutral antagonists
belong to the benzodioxanyl ketone class, whereas partial agonists
belong to different chemical classes. We found only two inverse
agonists, GR 125487 and SB 207266, which are both indoles. Analysis of
pharmacological characteristics of the constitutively active wild-type
and constitutively active mutated receptors revealed that 1) the ratio
between the efficiencies of the full agonist 5-HT and the partial
agonist RS 23597 was invariable when the receptor density increased,
but was dependent on receptor structure; 2) similarly, the efficacy of
the inverse agonist SB 207266 was not dependent on receptor density but
was dependent on receptor structure; 3) when the receptor concentration increased, the EC50 values of the full agonist 5-HT were
not modified and the increase in basal constitutive activity, as well
as its stimulation by 5-HT, followed a parallel evolution; and 4) the stimulation of basal constitutive activity by 5-HT was not modified by
the overexpression of G
s. All these results indicate that in COS-7
cells, the coupling of the 5-HT4 receptor to adenylyl cyclase was linear with no indication of spare receptors even at high
receptor density (8 pmol/mg). These results are also in accordance with
a precoupling between the activated receptor
(fR*) and adenylyl cyclase. Such
observations allowed us to use the two-state model to calculate the
constant J, i.e., the equilibrium allosteric constant denoting the
ratio of the receptor in the inactive versus active state (J = [R]/[R*]). We found that J was a receptor structural
characteristic, independent of receptor density.
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