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Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of "selective" antagonists.

par Sohy, Denis ;Yano, Hideaki;De Nadai, Patricia ;Urizar Andrieu, Eneko ;Guillabert, Aude ;Javitch, Jonathan A;Parmentier, Marc ;Springael, Jean-Yves
Référence The Journal of biological chemistry, 284, 45, page (31270-31279)
Publication Publié, 2009-11

Article révisé par les pairs

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Résumé :

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 alpha, demonstrating that cross-inhibition by antagonists also occurs in vivo. 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 in vivo.