title: Biased signaling at chemokine receptors.
abstract: The ability of G protein-coupled receptors (GPCRs) to activate selective signaling pathways according to the conformation stabilized by bound ligands (signaling bias) is a challenging concept in the GPCR field. Signaling bias has been documented for several GPCRs, including chemokine receptors. However, most of these studies examined the global signaling bias between G protein- and arrestin-dependent pathways, leaving unaddressed the potential bias between particular G protein subtypes. Here, we investigated the coupling selectivity of chemokine receptors CCR2, CCR5, and CCR7 in response to various ligands with G protein subtypes by using bioluminescence resonance energy transfer biosensors monitoring directly the activation of G proteins. We also compared data obtained with the G protein biosensors with those obtained with other functional readouts, such as β-arrestin-2 recruitment, cAMP accumulation, and calcium mobilization assays. We showed that the binding of chemokines to CCR2, CCR5, and CCR7 activated the three Gαi subtypes (Gαi1, Gαi2, and Gαi3) and the two Gαo isoforms (Gαoa and Gαob) with potencies that generally correlate to their binding affinities. In addition, we showed that the binding of chemokines to CCR5 and CCR2 also activated Gα12, but not Gα13. For each receptor, we showed that the relative potency of various agonist chemokines was not identical in all assays, supporting the notion that signaling bias exists at chemokine receptors.
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Corbisier
authors.affiliation: the Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galès
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Huszagh
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and Welbio, Université Libre de Bruxelles, B-1070 Brussels, Belgium and.
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
authors.affiliation: From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and jyspring@ulb.ac.be.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Springael
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D015374:Biosensing Techniques; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008163:Luminescent Measurements; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; C584933:CCR5 protein, human; C515370:CCR7 protein, human; D044385:GTP-Binding Protein alpha Subunits; D008024:Ligands; D021122:Protein Subunits; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D002118:Calcium
keywords: Bioluminescence Resonance Energy Transfer (BRET); Biosensor; Chemokine; G Protein-coupled Receptor (GPCR); Signaling