2. Academic Validation
  3. Location bias contributes to functionally selective responses of biased CXCR3 agonists

Location bias contributes to functionally selective responses of biased CXCR3 agonists

  • Nat Commun. 2022 Oct 4;13(1):5846. doi: 10.1038/s41467-022-33569-2.
Dylan Scott Eiger 1,  Noelia Boldizsar 2,  Christopher Cole Honeycutt 2,  Julia Gardner 2,  Stephen Kirchner 3 4,  Chloe Hicks 2,  Issac Choi 5,  Uyen Pham 1,  Kevin Zheng 6,  Anmol Warman 2,  Jeffrey S Smith 6 7 8 9 10,  Jennifer Y Zhang 3 11,  Sudarshan Rajagopal 12 13
Affiliations

Affiliations

  • 1 Department of Biochemistry, Duke University, Durham, NC, 27710, USA.
  • 2 Trinity College, Duke University, Durham, NC, 27710, USA.
  • 3 Department of Dermatology, Duke University, Durham, NC, 27707, USA.
  • 4 Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, 27707, USA.
  • 5 Department of Medicine, Duke University, Durham, NC, 27710, USA.
  • 6 Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 8 Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
  • 9 Dermatology Program, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 10 Department of Dermatology, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 11 Department of Pathology, Duke University, Durham, NC, 27710, USA.
  • 12 Department of Biochemistry, Duke University, Durham, NC, 27710, USA. [email protected].
  • 13 Department of Medicine, Duke University, Durham, NC, 27710, USA. [email protected].
PMID: 36195635 DOI: 10.1038/s41467-022-33569-2
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.

Figures