Constitutive activity of the human beta(1)-adrenergic receptor in
beta(1)-receptor transgenic mice
Mol Pharmacol, 60 (4):
712-7 (October 2001)Engelhardt, S Grimmer, Y Fan, G H Lohse, M J Research Support, Non-U.S.
Gov't United States Molecular pharmacology Mol Pharmacol. 2001 Oct;60(4):712-7..Abstract
We tested the hypothesis that the human beta(1)-adrenergic receptor
displays constitutive activity and that beta-adrenergic antagonists
differ in their ability to modulate this constitutive activity. Transfection
of the cDNAs of the human beta(1)- and beta(2)-adrenergic receptors
into COS-7 cells caused increases in basal cAMP that were proportional
to the receptor levels, thus demonstrating constitutive activity
for both subtypes. At comparable receptor levels, the increase in
basal cAMP was about 5-fold higher for the beta(2)- than for the
beta(1)-subtype. As a model for enhanced beta-adrenergic signaling
at the whole-organ level, we used transgenic mice with heart-specific
overexpression of the human beta(1)-adrenergic receptor. In this
model, the beta(1)-adrenergic receptor displayed constitutive activity
as evidenced by a higher spontaneous beating rate of isolated right
atria from beta(1)-transgenic versus wild-type mice. This difference
was abolished by the addition of CGP20712A, demonstrating inverse
agonist properties of this compound. We then tested whether various
beta-adrenergic antagonists currently in clinical use for the treatment
of heart failure differ in their ability to modulate constitutive
activity of the cardiac beta(1)-adrenergic receptor. The beta(1)-selective
antagonists metoprolol and bisoprolol showed significant inverse
agonist activity at the beta(1)-adrenergic receptor. Carvedilol behaved
as a neutral antagonist and xamoterol displayed marked partial agonist
activity. We conclude that the human beta(1)-adrenergic receptor
displays constitutive activity that is considerably lower than that
of the beta(2)-subtype. beta-Adrenergic antagonists currently in
clinical use differ in their ability to exert inverse agonist activity
at the human beta(1)-adrenergic receptor, which may contribute to
their therapeutic effects.