Divergent agonist selectivity in activating beta(1)- and beta(2)-adrenoceptors for G-protein and arrestin coupling

作者：Casella Ida; Ambrosio Caterina; Gro Maria Cristina; Molinari Paola; Costa Tommaso^*

来源：Biochemical Journal, 2011, 438: 191-202.

DOI：10.1042/BJ20110374

• beta-adrenoceptor
• beta-arrestin-2
• G-protein-coupled receptor (GPCR)
• ligand efficacy
• protein-protein interaction
• resonance energy transfer

The functional selectivity of adrenergic ligands for activation of beta 1- and beta 2-AR (adrenoceptor) subtypes has been extensively studied in cAMP signalling. Much less is known about ligand selectivity for arrestin-mediated signalling pathways. In the present study we used resonance energy transfer methods to compare the ability of beta 1- and beta 2-ARs to form a complex with the G-protein beta-subunit or beta-arrestin-2 in response to a variety of agonists with various degrees of efficacy. The profiles of beta 1-/beta 2-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 beta 2-AR, whereas for arrestin coupling the relationship was reversed. These data indicate that the beta 1-AR interacts more efficiently than beta 2-AR with arrestin, but less efficiently than beta 2-AR with G-protein. A group of ligands exhibited beta 1-AR-selective efficacy in driving the coupling to arrestin. Dobutamine, a member of this group, had 70% of the adrenaline (epinephrine) effect on arrestin via beta 1-AR, but acted as a competitive antagonist of adrenaline via beta 2-AR. Thus the structure of such ligands appears to induce an arrestin-interacting form of the receptor only when bound to the beta 1-AR subtype.

• 出版日期2011-8-15