PT  - JOURNAL ARTICLE
AU  - S. Daniele
AU  - M. L. Trincavelli
AU  - P. Gabelloni
AU  - D. Lecca
AU  - P. Rosa
AU  - M. P. Abbracchio
AU  - C. Martini
TI  - Agonist-Induced Desensitization/Resensitization of Human G Protein-Coupled Receptor 17: A Functional Cross-Talk between Purinergic and Cysteinyl-Leukotriene Ligands
AID  - 10.1124/jpet.110.178715
DP  - 2011 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 559--567
VI  - 338
IP  - 2
4099  - http://jpet.aspetjournals.org/content/338/2/559.short
4100  - http://jpet.aspetjournals.org/content/338/2/559.full
SO  - J Pharmacol Exp Ther2011 Aug 01; 338
AB  - G protein-coupled receptor (GPR) 17 is a P2Y-like receptor that responds to both uracil nucleotides (as UDP-glucose) and cysteinyl-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 exposure. In this study, we investigated in GPR17-expressing 1321N1 cells the cross-regulation between purinergic- and cysLT-mediated responses and analyzed GPR17 regulation after prolonged agonist exposure. Because GPR17 receptors couple to Gi proteins and adenylyl cyclase inhibition, both guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) 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 GPR17 loss of response (homologous desensitization) with similar kinetics. GPR17 homologous desensitization was accompanied by internalization of receptors inside cells, which occurred in a time-dependent manner with similar kinetics for both agonists. Upon agonist removal, receptor resensitization occurred with the typical kinetics of G protein-coupled receptors. Finally, activation of GPR17 by UDP-glucose (but not vice versa) induced a partial heterologous desensitization of LTD4-mediated responses, suggesting that nucleotides have a hierarchy in producing desensitizing signals. These findings suggest a functional cross-talk between purinergic and cysLT ligands at GPR17. Because of the recently suggested key role of GPR17 in brain oligodendrogliogenesis and myelination, this cross-talk may have profound implications in fine-tuning cell responses to demyelinating and inflammatory conditions when these ligands accumulate at lesion sites.