Research ArticleGPCR SIGNALING

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation

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Sci. Signal.  06 Nov 2018:
Vol. 11, Issue 555, eaaq1075
DOI: 10.1126/scisignal.aaq1075

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Biased chemokine responses

Like many other G protein–coupled receptors (GPCRs), chemokine receptors exhibit so-called biased agonism, whereby different ligands can stimulate either G protein– or β-arrestin–dependent signaling. Smith et al. investigated biased signaling by the receptor CXCR3, which directs T cell migration to sites of inflammation. The authors found that topical application of a small-molecule agonist that was β-arrestin biased, but not one that was G protein biased, exacerbated inflammation in a mouse model of contact hypersensitivity. The β-arrestin–biased agonist was more potent at stimulating mouse and human T cell chemotaxis in vitro and activated the kinase Akt, which promoted migration. Together, these data suggest that biased agonists of CXCR3, and perhaps other chemokine receptors, result in different physiological outcomes.