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beta-arrestin-biased agonism at the beta2-adrenergic receptor.

Publication ,  Journal Article
Drake, MT; Violin, JD; Whalen, EJ; Wisler, JW; Shenoy, SK; Lefkowitz, RJ
Published in: J Biol Chem
February 29, 2008

Classically, the beta 2-adrenergic receptor (beta 2AR) 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 beta 2AR, can signal via beta-arrestin-dependent pathways independent of G protein activation. It is currently unclear if among beta 2AR agonists there exist ligands that disproportionately signal via G proteins or beta-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 beta 2AR agonists exhibit relative efficacies for beta-arrestin-associated activities (beta-arrestin membrane translocation and beta 2AR internalization) identical to the irrelative efficacies for G protein-dependent signaling (cyclic AMP generation). However, for three betaAR ligands there is a marked bias toward beta-arrestin signaling; these ligands stimulate beta-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 alpha-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 beta-arrestin-mediated signaling.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 29, 2008

Volume

283

Issue

9

Start / End Page

5669 / 5676

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Protein Transport
  • Ligands
  • Humans
  • GTP-Binding Proteins
  • Fluorescence Resonance Energy Transfer
  • Cyclic AMP
  • Cell Membrane
 

Citation

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Drake, M. T., Violin, J. D., Whalen, E. J., Wisler, J. W., Shenoy, S. K., & Lefkowitz, R. J. (2008). beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem, 283(9), 5669–5676. https://doi.org/10.1074/jbc.M708118200
Drake, Matthew T., Jonathan D. Violin, Erin J. Whalen, James W. Wisler, Sudha K. Shenoy, and Robert J. Lefkowitz. “beta-arrestin-biased agonism at the beta2-adrenergic receptor.J Biol Chem 283, no. 9 (February 29, 2008): 5669–76. https://doi.org/10.1074/jbc.M708118200.
Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ. beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem. 2008 Feb 29;283(9):5669–76.
Drake, Matthew T., et al. “beta-arrestin-biased agonism at the beta2-adrenergic receptor.J Biol Chem, vol. 283, no. 9, Feb. 2008, pp. 5669–76. Pubmed, doi:10.1074/jbc.M708118200.
Drake MT, Violin JD, Whalen EJ, Wisler JW, Shenoy SK, Lefkowitz RJ. beta-arrestin-biased agonism at the beta2-adrenergic receptor. J Biol Chem. 2008 Feb 29;283(9):5669–5676.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 29, 2008

Volume

283

Issue

9

Start / End Page

5669 / 5676

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Adrenergic, beta-2
  • Protein Transport
  • Ligands
  • Humans
  • GTP-Binding Proteins
  • Fluorescence Resonance Energy Transfer
  • Cyclic AMP
  • Cell Membrane