Pairing orphan G protein-coupled receptors (GPCRs) with their cognate endogenous ligands is expected to have a major impact on our understanding of GPCR biology. It follows that reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as dualistic uracil-nucleotide/cysteinyl-leukotriene receptor and by others as inactive towards these stimuli altogether. Whilst regulation of central nervous system (CNS) myelination by GPR17 is well established, verification of activity of its putative endogenous ligands has proven elusive so far. Herein we report that uracil-nucleotides and cysteinyl-leukotrienes do not activate human, mouse or rat GPR17 in various cellular backgrounds including primary cells, using eight distinct functional assay platforms based on label-free pathway-unbiased biosensor technologies as well as canonical second messenger or biochemical assays. Appraisal of GPR17 activity can neither be accomplished with co-application of both ligand classes, nor with exogenous transfection of partner receptors (nucleotide P2Y12, cysteinyl-leukotriene CysLT1) to reconstitute the elusive pharmacology. Moreover, our study does not support inhibition of GPR17 by the marketed antiplatelet drugs cangrelor and ticagrelor, previously suggested to antagonize GPR17. Whereas our data do not disagree with a role of GPR17 per se as orchestrator of central nervous system functions, they challenge the utility of the above proposed (ant)agonists as tools to imply direct contribution of GPR17 in complex biological settings.
- The American Society for Pharmacology and Experimental Therapeutics