Agonist-Induced Desensitization/Resensitization of Human G Protein-Coupled Receptor 17: A Functional Cross-Talk between Purinergic and Cysteinyl-Leukotriene Ligands

G protein-coupled receptor (GPR) 17 is a P2Y-like receptor that responds to both uracil nucleotides (as UDP-glucose) and cys- teinyl-leukotrienes (cysLTs, as LTD4). By bioinformatic analysis, two distinct binding sites have been hypothesized to be present on GPR17, but little is known on their putative cross-regulation and on GPR17 desensitization/resensitization upon agonist ex- posure. In this study, we investigated in GPR17-expressing 1321N1 cells the cross-regulation between purinergic- and cysLT-mediated responses and analyzed GPR17 regulation af- ter prolonged agonist exposure. Because GPR17 receptors couple to Gi proteins and adenylyl cyclase inhibition, both guanosine 5?-O-(3-[35S]thio)triphosphate ([35S]GTP?S) binding and the cAMP assay have been used to investigate receptor functional activity. UDP-glucose was found to enhance LTD4 potency in mediating activation of G proteins and vice versa, possibly through an allosteric mechanism. Both UDP-glucose and LTD4 induced a time- and concentration-dependent