title: Divergent agonist selectivity in activating β1- and β2-adrenoceptors for G-protein and arrestin coupling.
abstract: The functional selectivity of adrenergic ligands for activation of β1- and β2-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 β1- and β2-ARs to form a complex with the G-protein β-subunit or β-arrestin-2 in response to a variety of agonists with various degrees of efficacy. The profiles of β1-/β2-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 β2-AR, whereas for arrestin coupling the relationship was reversed. These data indicate that the β1-AR interacts more efficiently than β2-AR with arrestin, but less efficiently than β2-AR with G-protein. A group of ligands exhibited β1-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 β1-AR, but acted as a competitive antagonist of adrenaline via β2-AR. Thus the structure of such ligands appears to induce an arrestin-interacting form of the receptor only when bound to the β1-AR subtype.
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Casella
authors.forename: Caterina
authors.initials: C
authors.lastname: Ambrosio
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Grò
authors.forename: Paola
authors.initials: P
authors.lastname: Molinari
authors.forename: Tommaso
authors.initials: T
authors.lastname: Costa
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D019393:Arrestin / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D019393:Arrestin; D002395:Catecholamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000246:Adenosine Diphosphate Ribose; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs