Distinct receptor domains determine subtype-specific coupling and desensitization phenotypes for human beta1- and beta2-adrenergic receptors.

Human beta1- and beta2-adrenergic receptor (beta1 AR and beta2 AR) coupling and desensitization characteristics were compared in defined heterologous expression systems. Significant differences in the coupling efficacies of the two subtypes were found in both Chinese hamster fibroblasts and murine Ltk- fibroblasts, which were used as surrogate cell lines. At the maximal level of stimulation with the nonselective beta-adrenergic agonist isoproterenol, beta1 AR-mediated adenylyl cyclase activation represented 70% and 20% of that mediated by beta2 AR in Chinese hamster and murine Ltk- fibroblasts, respectively. Sustained (15 min) stimulation with subsaturating concentration of isoproterenol (< 10% of receptor occupancy) led to identical desensitization of the beta-adrenergic-stimulated adenylyl cyclase activity for both beta1 AR and beta2AR-expressing cells. In contrast, when a nearly saturating concentration of isoproterenol (> 90% of receptor occupancy) was used to promote desensitization, the extent of desensitization observed for beta2 AR-expressing cells was 1.7-2-fold higher than that of the beta1 AR. The carboxyl domain of several G protein-coupled receptors has been shown to play important roles in both coupling efficacy and agonist-promoted desensitization. Therefore, we examined the contribution of this receptor domain in the subtype-selective phenotypes described above. A chimeric receptor composed of the first six transmembrane domains of the beta1 AR and of the seventh transmembrane domain and carboxyl tail of the beta2 AR maintained a coupling efficacy characteristic of the beta1 AR, whereas the extent of desensitization resulting from high receptor occupancy was identical to that of the beta2 AR. These results therefore suggest that the carboxyl portion of the beta1 AR and beta2 AR determines their subtype-selective desensitization patterns but not their respective coupling efficacies.