Location bias contributes to functionally selective responses of biased CXCR3 agonists.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Eiger, DS; Boldizsar, N; Honeycutt, CC; Gardner, J; Kirchner, S; Hicks, C; Choi, I; Pham, U; Zheng, K; Warman, A; Smith, JS; Zhang, JY; Rajagopal, S

Published Date

  • October 4, 2022

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 5846 -

PubMed ID

  • 36195635

Pubmed Central ID

  • PMC9532441

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-33569-2


  • eng

Conference Location

  • England