title: Probing Biased Signaling in Chemokine Receptors.
abstract: The chemokine system mediates leukocyte migration during homeostatic and inflammatory processes. Traditionally, it is described as redundant and promiscuous, with a single chemokine ligand binding to different receptors and a single receptor having several ligands. Signaling of chemokine receptors occurs via two major routes, G protein- and β-arrestin-dependent, which can be preferentially modulated depending on the ligands or receptors involved, as well as the cell types or tissues in which the signaling event occurs. The preferential activation of a certain signaling pathway to the detriment of others has been termed signaling bias and can accordingly be grouped into ligand bias, receptor bias, and tissue bias. Bias has so far been broadly overlooked in the process of drug development. The low number of currently approved drugs targeting the chemokine system, as well as the broad range of failed clinical trials, reflects the need for a better understanding of the chemokine system. Thus, understanding the character, direction, and consequence of biased signaling in the chemokine system may aid the development of new therapeutics. This review describes experiments to assess G protein-dependent and -independent signaling in order to quantify chemokine system bias.
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; Faculty of Chemistry, Alexandru Ioan Cuza University of Iaşi, Iaşi, Romania.
authors.forename: Roxana-Maria
authors.initials: RM
authors.lastname: Amarandi
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Gertrud Malene
authors.initials: GM
authors.lastname: Hjortø
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Rosenkilde
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark. Electronic address: stefanieth@sund.ku.dk.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Karlshøj
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008967:Molecular Biology / Q000379:methods*; D058990:Molecular Targeted Therapy / Q000379:methods; D019707:Receptors, Chemokine / Q000032:analysis / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D018925:Chemokines; D008024:Ligands; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP
keywords: 7TMR; Bias; Chemokine system; Chemotaxis; ERK; GPCR; GTPγS; IP(3); Internalization; cAMP; β-Arrestin