Divergent agonist selectivity in activating beta1 and beta2-adrenoceptors for G protein and arrestin coupling
Résumé
The functional selectivity of adrenergic ligands for activation of beta1 and beta2 adrenoceptor (AR) subtypes has been extensively studied in cAMP signalling. Much less is known about ligand selectivity for arrestin-mediated signalling pathways. Here we used resonance energy transfer methods to compare the ability of beta1 and beta2 adrenoceptors to form a complex with the G proteins beta subunit or beta-arrestin 2 in response to a variety of agonists with varying degrees of efficacy. The profiles of beta1/beta2 AR selectivity of the ligands for the two receptor-transducer interactions were sharply different. For G protein coupling, the majority of ligands were more effective in activating the beta2-AR, whereas for arrestin coupling the relationship was reversed. These data indicate that the beta1-AR interacts more efficiently than beta2-AR with arrestin but less efficiently than beta2-AR with G protein. A group of ligands exhibited beta1-AR selective efficacy in driving the coupling to arrestin. Dobutamine, a member of this group, had 70% of the epinephrine effect on arrestin via beta1-AR, but acted as competitive antagonist of epinephrine via beta2-AR. Thus, the structure of such ligands appears to induce an arrestin-interacting form of the receptor only when bound to the beta1-adrenoceptor subtype.
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