Beta-Blockers Show Inverse Agonism to a Novel Constitutively Active Mutant of β1-Adrenoceptor

Abstract

We obtained a new mutant of the β1-adrenergic receptor (β1-AR) by point mutations that can constitutively activate β1-AR. Aspartate104 of the β1-AR in the 2nd transmembrane was replaced with alanine. The β1-AR mutant expressed in human embryonic kidney (HEK)-293 cells displayed high level of constitutive activity with respect to wild-type (P<0.05), which could be partially inhibited by some beta-blockers. The constitutive activity of the mutant was confirmed by the finding that the enhanced activity is dependent on the level of receptor expression. The results of this study might have interesting implications for future studies aiming at elucidating the activation process of the β1-AR as well as the mechanism of action of beta-blockers. Keywords:: β1-adrenoceptor, constitutive activity, overexpression, inverse agonism