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J. Biol. Chem. 285 (46): 36188-36198

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Signaling of the Endogenous Agonists at the β2-Adrenergic Receptor*Formula

Susanne Reiner{ddagger}, Manuela Ambrosio{ddagger}§, Carsten Hoffmann{ddagger}1, , and Martin J. Lohse{ddagger}

From the {ddagger}Institute of Pharmacology and Toxicology, Versbacher Strasse 9, D-97078 Würzburg, Germany and
the §Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy

ABSTRACT Back to Top

Abstract: The concept of "functional selectivity" or "biased signaling" suggests that a ligand can have distinct efficacies with regard to different signaling pathways. We have investigated the question of whether biased signaling may be related to distinct agonist-induced conformational changes in receptors using the β2-adrenergic receptor (β2AR) and its two endogenous ligands epinephrine and norepinephrine as a model system. Agonist-induced conformational changes were determined in a fluorescently tagged β2AR FRET sensor. In this β2AR sensor, norepinephrine caused signals that amounted to only {approx}50% of those induced by epinephrine and the standard "full" agonist isoproterenol. Furthermore, norepinephrine-induced changes in the β2AR FRET sensor were slower than those induced by epinephrine (rate constants, 47 versus 128 ms). A similar partial β2AR activation signal was revealed for the synthetic agonists fenoterol and terbutaline. However, norepinephrine was almost as efficient as epinephrine (and isoproterenol) in causing activation of Gs and adenylyl cyclase. In contrast, fenoterol was quite efficient in triggering β-arrestin2 recruitment to the cell surface and its interaction with β2AR, as well as internalization of the receptors, whereas norepinephrine caused partial and slow changes in these assays. We conclude that partial agonism of norepinephrine at the β2AR is related to the induction of a different active conformation and that this conformation is efficient in signaling to Gs and less efficient in signaling to β-arrestin2. These observations extend the concept of biased signaling to the endogenous agonists of the β2AR and link it to distinct conformational changes in the receptor.

Key Words: Adrenergic Receptor • Fluorescence Resonance Energy Transfer (FRET) • G-protein-coupled Receptors (GPCR) • Microscopic Imaging • Signal Transduction

Received for publication August 16, 2010.

1 To whom correspondence should be addressed: Institut für Pharmakologie und Toxikologie, Versbacher Strasse 9, 97078 Würzburg, Germany. E-mail: C.Hoffmann{at}

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