Anales RANF

P.47 PHYSICAL AND FUNCTIONAL INTERACTION BETWEEN GPR17 AND THE CHEMOKINE RECEPTOR 2: A PROMISING TOOL FOR MANAGING REMYELINATION D. Pietrobono 1 , S. Daniele 1 , C. Parravicini 2 , I. Eberini 2 , C. Martini 1 , M.L. Trincavelli 1 1 University of Pisa, Pisa, Italy, 2 University of Milano, Milano, Italy The reconstitution of a functional myelin sheath in the central nervous system (CNS) is the cornerstone for the functional recovery in multiple sclerosis patients. Recent findings demonstrated that agonist compounds of the G-protein coupled receptor GPR17 can promote the activity of oligodendrocyte precursor cells (OPCs) towards CNS remyelination. Besides sugar nucleotides and leukotrienes, GPR17 can be promiscuously activated by pro-inflammatory oxysterols and chemokines released in demyelinating lesions, suggesting that a balanced interplay between GPR17 and the CXCR receptors may be central for OPC migration and successful remyelination. Herein, the chemokine receptor CXCR2 was selected to establish the structural and functional interactions with GPR17. In particular, the relative propensity of GPR17 and CXCR2 to form heterodimers was assessed by immunoenzymatic assay, and the ability of CXCR2 to modify GPR17 functionality and viceversa was investigated by determining the receptor-mediated modulation of intracellular cAMP. The CXCR2 and GPR17 receptors were found to physically interact in basal conditions. The receptor association was reduced in the presence of CXCR2 receptor ligands, and not affected by GPR17 receptor modulation. In contrast, when the GPR17 receptor agonist was combined with a CXCR2 antagonist, the significant decrease in GPR17- CXCR2 interaction persisted. GPR17 functionality was modulated by the presence of the CXCR2 receptor only when CXCR2 is blocked by its antagonist. In contrast, CXCR2 functionality was modulated when GPR17 is stimulated by its agonist. Overall, these results suggest that GPR17-CXCR2 interaction can be modulated differently by the activation or block of CXCR2 and confirm the importance of a functional interplay between the two receptors. Supported by FISM 2015 cod. 2015/R/11.