Biased Agonism as a Mechanism for Differential Signaling by Chemokine Receptors |
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Authors: | Sudarshan Rajagopal Daniel L Bassoni James J Campbell Norma P Gerard Craig Gerard Tom S Wehrman |
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Institution: | From the ‡Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.;§DiscoveRx Corporation, Fremont, California 94538.;¶Department of Dermatology, Brigham and Women''s Hospital, Boston, Massachusetts 02115, and ;‖Division of Respiratory Diseases, Department of Pediatrics, Children''s Hospital, Boston, Massachusetts 02115 |
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Abstract: | Chemokines display considerable promiscuity with multiple ligands and receptors shared in common, a phenomenon that is thought to underlie their biochemical “redundancy.” Their receptors are part of a larger seven-transmembrane receptor superfamily, commonly referred to as G protein-coupled receptors, which have been demonstrated to be able to signal with different efficacies to their multiple downstream signaling pathways, a phenomenon referred to as biased agonism. Biased agonism has been primarily reported as a phenomenon of synthetic ligands, and the biologic prevalence and importance of such signaling are unclear. Here, to assess the presence of biased agonism that may underlie differential signaling by chemokines targeting the same receptor, we performed a detailed pharmacologic analysis of a set of chemokine receptors with multiple endogenous ligands using assays for G protein signaling, β-arrestin recruitment, and receptor internalization. We found that chemokines targeting the same receptor can display marked differences in their efficacies for G protein- or β-arrestin-mediated signaling or receptor internalization. This ligand bias correlates with changes in leukocyte migration, consistent with different mechanisms underlying the signaling downstream of these receptors induced by their ligands. These findings demonstrate that biased agonism is a common and likely evolutionarily conserved biological mechanism for generating qualitatively distinct patterns of signaling via the same receptor in response to different endogenous ligands. |
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Keywords: | Arrestin Chemokines G Protein-coupled Receptors (GPCR) G Proteins Signaling Biased Agonism |
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