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Dynamic Regulation of CXCR1 and CXCR2 Homo- and Heterodimers¹

Laura Martínez Muñoz,^* Pilar Lucas,^* Gemma Navarro, Ana I. Checa,^* Rafael Franco, Carlos Martínez-A.,^* José Miguel Rodríguez-Frade,^* and Mario Mellado^2*

*Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Cantoblanco, Madrid, Spain; and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, and Department of Biochemistry and Molecular Biology, Universidad de Barcelona, Barcelona, Spain

Although homo- and heterodimerization are reported for some chemokine receptors, it remains unclear whether these functional states are in dynamic equilibrium and how receptor/ligand levels influence oligomerization. In human neutrophils and in cell lines that coexpress the chemokine receptors CXCR1 and CXCR2, we used fluorescence resonance energy transfer techniques to show that these two receptors form homo- and heterodimers. Receptor expression and ligand activation were found to regulate the balance between these complexes, adapting the response to changes in the milieu. CXCL8, a ligand for both receptors, alters heterodimeric complexes, whereas it stabilizes homodimers and promotes receptor internalization. Oligomerization of receptors, together with the regulation of their expression and desensitization, could thus contribute to the fine control of chemokine functions.

Correspondence: ² Address correspondence and reprint requests to Dr. Mario Mellado, Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Darwin 3, Campus de Cantoblanco. E-28049, Madrid, Spain. E-mail address: mmellado{at}cnb.uam.es

¹ This work was supported by the European Union (Innochem LSHB-CT-2005-518167; Molecular Imaging LSHG-CT-2003-503259), the Spanish Ministry of Science and Innovation (SAF2005-03388; SAF2008-02175), the Madrid Regional Government (CCG07-CSIC/SAL-1904), and the Redes temáticas de Investigación Cooperativa Sanitaria Program (RD08/0075 RIER; Instituto de Salud Carlos III).