β-arrestin-biased agonism at the β2-adrenergic receptor

Matthew T. Drake, Jonathan D. Violin, Erin J. Whalen, James W. Wisler, Sudha K. Shenoy, Robert J. Lefkowitz

Research output: Contribution to journalArticle

197 Scopus citations

Abstract

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 their relative 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 α-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.

Original languageEnglish (US)
Pages (from-to)5669-5676
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number9
DOIs
StatePublished - Feb 29 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Drake, M. T., Violin, J. D., Whalen, E. J., Wisler, J. W., Shenoy, S. K., & Lefkowitz, R. J. (2008). β-arrestin-biased agonism at the β2-adrenergic receptor. Journal of Biological Chemistry, 283(9), 5669-5676. https://doi.org/10.1074/jbc.M708118200