Efficacy of β1-adrenergic receptors is lower than that of β2-adrenergic receptors

Abstract

We investigated the relative activity at which fully occupied human β1- and β2-adrenergic receptors (β1AR and β2AR) activate the stimulatory G protein (Gs)/adenylyl cyclase (AC) system in isolated membranes. The receptors were cloned and coexpressed in permanent cell lines at β1/β2 ratios that varied from 1:2 to 3:1 and at total receptor abundance that ranged from 8 to 2200 fmol/mg of membrane protein. Cell lines expressing β1AR or β2AR alone were also obtained. Competitive inhibition of isoproterenol-stimulated AC activity by the β2-selective antagonist ICI 118551 showed in all cases that maximal stimulation elicited by β1AR was lower than when it was elicited by equivalent densities of β2AR. This was especially noticeable at limiting concentrations of receptor, where the β1AR-mediated effect was < 10% of that mediated by β2AR. At receptor concentrations > 1000 fmol/mg of protein, stimulation by β2AR appeared to reach a maximum, while stimulation by β1AR continued to increase, so that at 3200 fmol/mg, β1AR-stimulated activity was 80% of β2AR-stimulated activity. It is clear that the degree to which a given receptor system is able to activate the Gs/AC system depends not only on its abundance but also on an activity parameter determined by the nature of the receptor, which we refer to as receptor efficacy. For human βARs, this efficacy parameter is much lower for the β1 subtype than for its β2 counterpart. The more effective stimulation of AC through β2AR than through β1AR is an inherent property of the receptor and not the cell in which it is expressed.