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J. Biol. Chem., Vol. 283, Issue 9, 5669-5676, February 29, 2008

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β-Arrestin-biased Agonism at the β₂-Adrenergic Receptor^*

Matthew T. Drake¹, Jonathan D. Violin², Erin J. Whalen, James W. Wisler³, Sudha K. Shenoy, and Robert J. Lefkowitz, An investigator of the Howard Hughes Medical Institute^¶4

From the Departments of Medicine and Biochemistry and the ^¶Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710

Classically, the β₂-adrenergic receptor (β₂AR) and other members of the seven-transmembrane receptor (7TMR) superfamily activate G protein-dependent signaling pathways in response to ligand stimulus. It has recently been discovered, however, that a number of 7TMRs, including β₂AR, can signal via β-arrestin-dependent pathways independent of G protein activation. It is currently unclear if among β₂AR agonists there exist ligands that disproportionately signal via G proteins or β-arrestins and are hence "biased." Using a variety of approaches that include highly sensitive fluorescence resonance energy transfer-based methodologies, including a novel assay for receptor internalization, we show that the majority of known β₂AR agonists exhibit relative efficacies for β-arrestin-associated activities (β-arrestin membrane translocation and β₂AR internalization) identical to the irrelative efficacies for G protein-dependent signaling (cyclic AMP generation). However, for three βAR ligands there is a marked bias toward β-arrestin signaling; these ligands stimulate β-arrestin-dependent receptor activities to a much greater extent than would be expected given their efficacy for G protein-dependent activity. Structural comparison of these biased ligands reveals that all three are catecholamines containing an ethyl substitution on the -carbon, a motif absent on all of the other, unbiased ligands tested. Thus, these studies demonstrate the potential for developing a novel class of 7TMR ligands with a distinct bias for β-arrestin-mediated signaling.

Received for publication, September 28, 2007 , and in revised form, December 5, 2007.

^* This work was supported in part by National Institutes of Health Grants RO1 HL16037 and RO1 HL70631 (to R. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Div. of Endocrinology, Mayo Clinic College of Medicine, 200 First St. S. W., Rochester, MN 55905.

² Recipient of an American Heart Association post-doctoral fellowship.

³ Supported by a Sarnoff Cardiovascular Research Foundation fellowship.

⁴ To whom correspondence should be addressed: Howard Hughes Medical Inst., Duke University Medical Center, Box 3821, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.

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