Understanding the mechanism of biased agonism at chemokine receptors (1066.17)

Chemokines display considerable promiscuity with multiple ligands and receptors shared in common. Their receptors are G protein-coupled receptors (GPCRs), which are capable of signaling with different efficacies to their multiple downstream pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands and the biologic importance of such signaling is unclear. To assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a pharmacologic analysis of a set of chemokine receptors using assays for G protein signaling, β-arrestin (βarr) recruitment and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or βarr-mediated signaling or receptor internalization. Moreover, some chemokine receptors display significant bias for all their ligands, acting as "biased receptors". Ligand...