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Location bias contributes to functionally selective responses of biased CXCR3 agonists

Author

Listed:
  • Dylan Scott Eiger

    (Duke University)

  • Noelia Boldizsar

    (Duke University)

  • Christopher Cole Honeycutt

    (Duke University)

  • Julia Gardner

    (Duke University)

  • Stephen Kirchner

    (Duke University
    Duke University)

  • Chloe Hicks

    (Duke University)

  • Issac Choi

    (Duke University)

  • Uyen Pham

    (Duke University)

  • Kevin Zheng

    (Harvard Medical School)

  • Anmol Warman

    (Duke University)

  • Jeffrey S. Smith

    (Harvard Medical School
    Brigham and Women’s Hospital
    Beth Israel Deaconess Medical Center
    Boston Children’s Hospital)

  • Jennifer Y. Zhang

    (Duke University
    Duke University)

  • Sudarshan Rajagopal

    (Duke University
    Duke University)

Abstract

Some G protein-coupled receptor (GPCR) ligands act as “biased agonists” that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.

Suggested Citation

  • Dylan Scott Eiger & Noelia Boldizsar & Christopher Cole Honeycutt & Julia Gardner & Stephen Kirchner & Chloe Hicks & Issac Choi & Uyen Pham & Kevin Zheng & Anmol Warman & Jeffrey S. Smith & Jennifer Y, 2022. "Location bias contributes to functionally selective responses of biased CXCR3 agonists," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33569-2
    DOI: 10.1038/s41467-022-33569-2
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    References listed on IDEAS

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    1. Naomi R. Latorraca & Jason K. Wang & Brian Bauer & Raphael J. L. Townshend & Scott A. Hollingsworth & Julia E. Olivieri & H. Eric Xu & Martha E. Sommer & Ron O. Dror, 2018. "Molecular mechanism of GPCR-mediated arrestin activation," Nature, Nature, vol. 557(7705), pages 452-456, May.
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    1. Shane C. Wright & Aikaterini Motso & Stefania Koutsilieri & Christian M. Beusch & Pierre Sabatier & Alessandro Berghella & Élodie Blondel-Tepaz & Kimberley Mangenot & Ioannis Pittarokoilis & Despoina-, 2023. "GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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