RT Journal Article
SR Electronic
T1 Constitutive Activity of the Human β<sub>1</sub>-Adrenergic Receptor in β<sub>1</sub>-Receptor Transgenic Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 712
OP 717
VO 60
IS 4
A1 Stefan Engelhardt
A1 Yvonne Grimmer
A1 Guo-Huang Fan
A1 Martin J. Lohse
YR 2001
UL http://molpharm.aspetjournals.org/content/60/4/712.abstract
AB We tested the hypothesis that the human β1-adrenergic receptor displays constitutive activity and that β-adrenergic antagonists differ in their ability to modulate this constitutive activity. Transfection of the cDNAs of the human β1- and β2-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 β2- than for the β1-subtype. As a model for enhanced β-adrenergic signaling at the whole-organ level, we used transgenic mice with heart-specific overexpression of the human β1-adrenergic receptor. In this model, the β1-adrenergic receptor displayed constitutive activity as evidenced by a higher spontaneous beating rate of isolated right atria from β1-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 β-adrenergic antagonists currently in clinical use for the treatment of heart failure differ in their ability to modulate constitutive activity of the cardiac β1-adrenergic receptor. The β1-selective antagonists metoprolol and bisoprolol showed significant inverse agonist activity at the β1-adrenergic receptor. Carvedilol behaved as a neutral antagonist and xamoterol displayed marked partial agonist activity. We conclude that the human β1-adrenergic receptor displays constitutive activity that is considerably lower than that of the β2-subtype. β-Adrenergic antagonists currently in clinical use differ in their ability to exert inverse agonist activity at the human β1-adrenergic receptor, which may contribute to their therapeutic effects. The American Society for Pharmacology and Experimental Therapeutics