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.
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Research Article|
July 27 2011
Divergent agonist selectivity in activating β1- and β2-adrenoceptors for G-protein and arrestin coupling
Ida Casella;
Ida Casella
1
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
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Caterina Ambrosio;
Caterina Ambrosio
1
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
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Maria Cristina Grò;
Maria Cristina Grò
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
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Paola Molinari;
Paola Molinari
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
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Tommaso Costa
Tommaso Costa
2
1Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy
2To whom correspondence should be addressed (email tomcosta@iss.it).
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Publisher: Portland Press Ltd
Received:
February 28 2011
Revision Received:
May 03 2011
Accepted:
May 11 2011
Accepted Manuscript online:
May 11 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (1): 191–202.
Article history
Received:
February 28 2011
Revision Received:
May 03 2011
Accepted:
May 11 2011
Accepted Manuscript online:
May 11 2011
Citation
Ida Casella, Caterina Ambrosio, Maria Cristina Grò, Paola Molinari, Tommaso Costa; Divergent agonist selectivity in activating β1- and β2-adrenoceptors for G-protein and arrestin coupling. Biochem J 15 August 2011; 438 (1): 191–202. doi: https://doi.org/10.1042/BJ20110374
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