Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the Protean Effects of âSelectiveâ Antagonists Export

@article{citeulike:5900607, abstract = {10.1074/jbc.M109.054809 Chemokine receptors constitute an attractive family of drug targets in the frame of inflammatory diseases. However, targeting specific chemokine receptors may be complicated by their ability to form dimers or higher order oligomers. Using a combination of luminescence complementation and bioluminescence resonance energy transfer assays, we demonstrate for the first time the existence of hetero-oligomeric complexes composed of at least three chemokine receptors (CCR2, CCR5, and CXCR4). We show in T cells and monocytes that negative binding cooperativity takes place between the binding pockets of these receptors, demonstrating their functional interaction in leukocytes. We also show that specific antagonists of one receptor (TAK-779 or AMD3100) lead to functional cross-inhibition of the others. Finally, using the air pouch model in mice, we show that the CCR2 and CCR5 antagonist TAK-779 inhibits cell recruitment promoted by the CXCR4 agonist SDF-1\^{I}±, demonstrating that cross-inhibition by antagonists also occurs . Thus, antagonists of the therapeutically important chemokine receptors regulate the functional properties of other receptors to which they do not bind directly with important implications for the use of these agents .}, author = {Sohy, Denis and Yano, Hideaki and de Nadai, Patricia and Urizar, Eneko and Guillabert, Aude and Javitch, Jonathan A. and Parmentier, Marc and Springael, Jean-Yves}, booktitle = {Journal of Biological Chemistry}, citeulike-article-id = {5900607}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M109.054809}, citeulike-linkout-1 = {http://www.jbc.org/content/284/45/31270.abstract}, citeulike-linkout-2 = {http://www.jbc.org/content/284/45/31270.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19758998}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19758998}, day = {6}, doi = {10.1074/jbc.M109.054809}, issn = {1083-351X}, journal = {The Journal of biological chemistry}, keywords = {antagonist, chemokine, drug, oligomerization}, month = {November}, number = {45}, pages = {31270--31279}, posted-at = {2009-10-06 19:26:05}, priority = {2}, title = {Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the Protean Effects of \^{a}€œSelective\^{a}€ Antagonists}, url = {http://dx.doi.org/10.1074/jbc.M109.054809}, volume = {284}, year = {2009} }

TY - JOUR ID - citeulike:5900607 L3 - citeulike-article-id:5900607 N2 - 10.1074/jbc.M109.054809 Chemokine receptors constitute an attractive family of drug targets in the frame of inflammatory diseases. However, targeting specific chemokine receptors may be complicated by their ability to form dimers or higher order oligomers. Using a combination of luminescence complementation and bioluminescence resonance energy transfer assays, we demonstrate for the first time the existence of hetero-oligomeric complexes composed of at least three chemokine receptors (CCR2, CCR5, and CXCR4). We show in T cells and monocytes that negative binding cooperativity takes place between the binding pockets of these receptors, demonstrating their functional interaction in leukocytes. We also show that specific antagonists of one receptor (TAK-779 or AMD3100) lead to functional cross-inhibition of the others. Finally, using the air pouch model in mice, we show that the CCR2 and CCR5 antagonist TAK-779 inhibits cell recruitment promoted by the CXCR4 agonist SDF-1α, demonstrating that cross-inhibition by antagonists also occurs . Thus, antagonists of the therapeutically important chemokine receptors regulate the functional properties of other receptors to which they do not bind directly with important implications for the use of these agents . IS - 45 JF - The Journal of biological chemistry SN - 1083-351X EP - 31279 TI - Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the Protean Effects of “Selective” Antagonists VL - 284 T2 - Journal of Biological Chemistry SP - 31270 KW - antagonist KW - chemokine KW - drug KW - oligomerization AU - Sohy, Denis AU - Yano, Hideaki AU - de Nadai, Patricia AU - Urizar, Eneko AU - Guillabert, Aude AU - Javitch, Jonathan AU - Parmentier, Marc AU - Springael, Jean-Yves PY - 2009/11/06/ UR - http://dx.doi.org/10.1074/jbc.M109.054809 ER -