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Biased agonism as a mechanism for differential signaling by chemokine receptors.

Publication ,  Journal Article
Rajagopal, S; Bassoni, DL; Campbell, JJ; Gerard, NP; Gerard, C; Wehrman, TS
Published in: J Biol Chem
December 6, 2013

Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical "redundancy." Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, β-arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or β-arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands.

Duke Scholars

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

December 6, 2013

Volume

288

Issue

49

Start / End Page

35039 / 35048

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Chemokine
  • Models, Biological
  • Ligands
  • Kinetics
  • Humans
  • HEK293 Cells
  • GTP-Binding Proteins
  • Chemokines
 

Citation

APA
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ICMJE
MLA
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Rajagopal, S., Bassoni, D. L., Campbell, J. J., Gerard, N. P., Gerard, C., & Wehrman, T. S. (2013). Biased agonism as a mechanism for differential signaling by chemokine receptors. J Biol Chem, 288(49), 35039–35048. https://doi.org/10.1074/jbc.M113.479113
Rajagopal, Sudarshan, Daniel L. Bassoni, James J. Campbell, Norma P. Gerard, Craig Gerard, and Tom S. Wehrman. “Biased agonism as a mechanism for differential signaling by chemokine receptors.J Biol Chem 288, no. 49 (December 6, 2013): 35039–48. https://doi.org/10.1074/jbc.M113.479113.
Rajagopal S, Bassoni DL, Campbell JJ, Gerard NP, Gerard C, Wehrman TS. Biased agonism as a mechanism for differential signaling by chemokine receptors. J Biol Chem. 2013 Dec 6;288(49):35039–48.
Rajagopal, Sudarshan, et al. “Biased agonism as a mechanism for differential signaling by chemokine receptors.J Biol Chem, vol. 288, no. 49, Dec. 2013, pp. 35039–48. Pubmed, doi:10.1074/jbc.M113.479113.
Rajagopal S, Bassoni DL, Campbell JJ, Gerard NP, Gerard C, Wehrman TS. Biased agonism as a mechanism for differential signaling by chemokine receptors. J Biol Chem. 2013 Dec 6;288(49):35039–35048.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

December 6, 2013

Volume

288

Issue

49

Start / End Page

35039 / 35048

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, Chemokine
  • Models, Biological
  • Ligands
  • Kinetics
  • Humans
  • HEK293 Cells
  • GTP-Binding Proteins
  • Chemokines