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2-Adrenoceptor on Ligand Affinity in Transgenic Mice
Department of Pharmacology and Clinical Pharmacology, Medical
Faculty of Ankara University, Ankara, Turkey (H.G., H.O.O.),
Department
of Pharmacological and Pharmaceutical Sciences, University of Houston,
Houston, Texas 72204 (R.A.B.), and
Department of Pharmacology,
MCP-Hahnemann School of Medicine, Allegheny University, Philadelphia,
Pennsylvania 19129 (H.G., M.D.J., E.F.)
In previous studies, it was shown that the overexpression of
2-adrenoceptor (2AR) in the hearts of
transgenic mice (Tg) leads to agonist-independent activation of
adenylate cyclase and enhanced myocardial function. Here, we measured
the physical coupling of 2AR and Gs by
evaluating the coimmunoprecipitation of 2AR and
Gs and the ligand binding properties of 2AR
in the hearts of Tg mice to investigate the details of the interaction
among ligand, receptor, and G protein. The following results were
obtained: (i) coimmunoprecipitation of 2AR and
Gs was increased in the absence of agonist in Tg mice
compared with the control animals. This demonstrates directly the
increased interaction between unliganded 2AR and
Gs, which is consistent with increased background cAMP production and cardiac function in the hearts of Tg mice. (ii) Guanosine-5
-(,
-imido)triphosphate abolished the association of
2AR/Gs in the immunoprecipitate. (iii) The
affinities for ligands that show agonist (isoproterenol, clenbuterol,
and dobutamine), neutral antagonist (alprenolol and timolol), and
negative antagonist (propranolol and ICI 118551) activities in this
experimental system were increased, not changed and decreased,
respectively, in Tg mice compared with the controls. (iv) This
efficacy-dependent alteration in ligand affinities was still observed
in the presence of a guanosine-5-(,-imido)triphosphate
concentration that abolishes 2AR/Gs
coupling. This suggests that the altered 2AR binding affinities in Tg mice are not due to the increased interaction between
2AR and Gs. These data cannot be explained
by using ternary, quinternary, two-state extended ternary, or cubic
ternary complex models. We therefore discuss the results using a
"two-state polymerization model" that includes an isomerization
step for the conversion of receptor between an inactive and an active
form (denoted as R and R*, respectively) and a polymerization of the
active state (R*n). The simplest form of this model (i.e.,
noncooperative dimerization of the receptor) is found to be consistent
with the experimental data.
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