PT  - JOURNAL ARTICLE
AU  - Dylan Scott Eiger
AU  - Noelia Boldizsar
AU  - Christopher Cole Honeycutt
AU  - Julia Gardner
AU  - Stephen Kirchner
AU  - Chloe Hicks
AU  - Issac Choi
AU  - Uyen Pham
AU  - Kevin Zheng
AU  - Anmol Warman
AU  - Jeffrey Smith
AU  - Jennifer Zhang
AU  - Sudarshan Rajagopal
TI  - Location bias contributes to functionally selective responses of biased CXCR3 agonists
AID  - 10.1101/2022.01.13.476255
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.13.476255
4099  - http://biorxiv.org/content/early/2022/01/14/2022.01.13.476255.short
4100  - http://biorxiv.org/content/early/2022/01/14/2022.01.13.476255.full
AB  - Some G protein-coupled receptor (GPCR) ligands act as “biased agonists” which 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 chemokine GPCR CXCR3. The signaling profile of CXCR3 changed as it trafficked from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling was critical for biased activation of G proteins, β-arrestins, and ERK1/2. In CD8+ T cells, the chemokines promoted unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation was 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.Competing Interest StatementThe authors have declared no competing interest.