Location bias contributes to functionally selective responses of biased CXCR3 agonists

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. Zhang and Sudarshan Rajagopal ()
Additional contact information
Dylan Scott Eiger: Duke University
Noelia Boldizsar: Duke University
Christopher Cole Honeycutt: Duke University
Julia Gardner: Duke University
Stephen Kirchner: 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
Jennifer Y. Zhang: Duke University
Sudarshan Rajagopal: Duke University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33569-2

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DOI: 10.1038/s41467-022-33569-2

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