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 beta1- and beta2-adrenergic receptors (beta1AR and beta2AR) activate the stimulatory G protein (G(s))/adenylyl cyclase (AC) system in isolated membranes. The receptors were cloned and coexpressed in permanent cell lines at beta1/beta2 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 fines expressing beta1AR or beta2AR alone were also obtained. Competitive inhibition of isoproterenol-stimulated AC activity by the beta2-selective antagonist ICI 118551 showed in all cases that maximal stimulation elicited by beta1AR was lower than when it was elicited by equivalent densities of beta2AR. This was especially noticeable at limiting concentrations of receptor, where the beta1AR-mediated effect was < 10% of that mediated by beta2AR. At receptor concentrations > 1000 fmol/mg of protein, stimulation by beta2AR appeared to reach a maximum, while stimulation by beta1AR continued to increase, so that at 3200 fmol/mg, beta1AR-stimulated activity was 80% of beta2AR-stimulated activity. It is clear that the degree to which a given receptor system is able to activate the G(s)/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 betaARs, this efficacy parameter is much lower for the beta1 subtype than for its beta2 counterpart. The more effective stimulation of AC through beta2AR than through beta1AR is an inherent property of the receptor and not the cell in which it is expressed.