Efficacy of beta 1-adrenergic receptors is lower than that of beta 2-adrenergic receptors.

We investigated the relative activity at which fully occupied human beta 1- and beta 2-adrenergic receptors (beta 1AR and beta 2AR) activate the stimulatory G protein (Gs)/adenylyl cyclase (AC) system in isolated membranes. The receptors were cloned and coexpressed in permanent cell lines at beta 1/beta 2 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 beta 1AR or beta 2AR alone were also obtained. Competitive inhibition of isoproterenol-stimulated AC activity by the beta 2-selective antagonist ICI 118551 showed in all cases that maximal stimulation elicited by beta 1AR was lower than when it was elicited by equivalent densities of beta 2AR. This was especially noticeable at limiting concentrations of receptor, where the beta 1AR-mediated effect was < 10% of that mediated by beta 2AR. At receptor concentrations > 1000 fmol/mg of protein, stimulation by beta 2AR appeared to reach a maximum, while stimulation by beta 1AR continued to increase, so that at 3200 fmol/mg, beta 1AR-stimulated activity was 80% of beta 2AR-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 beta ARs, this efficacy parameter is much lower for the beta 1 subtype than for its beta 2 counterpart. The more effective stimulation of AC through beta 2AR than through beta 1AR is an inherent property of the receptor and not the cell in which it is expressed.