Beta-blockers show inverse agonism to a novel constitutively active mutant of β₁-adrenoceptor

We obtained a new mutant of the β₁-adrenergic receptor (β₁-AR) by point mutations that can constitutively activate β₁-AR. Aspartate 104 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.