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 be ta1- 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 cel l 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 pro tein. Cell fines expressing beta1AR or beta2AR alone were also obtaine d. Competitive inhibition of isoproterenol-stimulated AC activity by t he beta2-selective antagonist ICI 118551 showed in all cases that maxi mal stimulation elicited by beta1AR was lower than when it was elicite d by equivalent densities of beta2AR. This was especially noticeable a t limiting concentrations of receptor, where the beta1AR-mediated effe ct was < 10% of that mediated by beta2AR. At receptor concentrations > 1000 fmol/mg of protein, stimulation by beta2AR appeared to reach a m aximum, while stimulation by beta1AR continued to increase, so that at 3200 fmol/mg, beta1AR-stimulated activity was 80% of beta2AR-stimulat ed activity. It is clear that the degree to which a given receptor sys tem is able to activate the G(s)/AC system depends not only on its abu ndance but also on an activity parameter determined by the nature of t he 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 b eta2AR than through beta1AR is an inherent property of the receptor an d not the cell in which it is expressed.