TY - JOUR T1 - Allosteric Modulation of Binding Properties between Units of Chemokine Receptor Homo- and Hetero-Oligomers JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1652 LP - 1661 DO - 10.1124/mol.105.019414 VL - 69 IS - 5 AU - Jean-Yves Springael AU - Phu Nguyen Le Minh AU - Eneko Urizar AU - Sabine Costagliola AU - Gilbert Vassart AU - Marc Parmentier Y1 - 2006/05/01 UR - http://molpharm.aspetjournals.org/content/69/5/1652.abstract N2 - We have demonstrated previously that the chemokine receptors CCR2 and CCR5 form homo- and heterodimers and that dimers can only bind a single chemokine molecule with high affinity. We provide here evidence from bioluminescence resonance energy transfer experiments that stimulation by chemokines does not influence the CCR2/CCR5 heterodimerization status. In addition, we show that the rate of radioligand dissociation from one unit of the heterodimer in “infinite” tracer dilution conditions is strongly increased in the presence of an unlabeled chemokine ligand of the other unit. These results demonstrate unambiguously that the interaction between heterodimer units is of allosteric nature. Agonists, but also some monoclonal antibodies, could promote such negative binding cooperativity, indicating that this phenomenon does not require the full conformational change associated with receptor activation. Finally, we show that G protein coupling is required for high-affinity binding of macrophage inflammatory protein-1β (CCL4) to CCR5 and that the dissociation from G proteins, after incubation with Gpp(NH)p, promotes the release of prebound radiolabeled chemokines with kinetics similar to those measured after the addition of an excess of unlabeled chemokines. These observations suggest that the association with G proteins probably participates in the negative cooperativity observed between receptor monomers. We propose that negative cooperativity within homo- and heterodimers of chemokine receptors and probably other G protein-coupled receptors will probably have major implications in their pharmacology in vivo and in the physiopathology of the diseases with which they are associated. ER -