The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes

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 the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations...

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Veröffentlicht in:Molecular pharmacology 2017-05, Vol.91 (5), p.518-532
Hauptverfasser: Simon, Katharina, Merten, Nicole, Schröder, Ralf, Hennen, Stephanie, Preis, Philip, Schmitt, Nina-Katharina, Peters, Lucas, Schrage, Ramona, Vermeiren, Celine, Gillard, Michel, Mohr, Klaus, Gomeza, Jesus, Kostenis, Evi
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container_end_page 532
container_issue 5
container_start_page 518
container_title Molecular pharmacology
container_volume 91
creator Simon, Katharina
Merten, Nicole
Schröder, Ralf
Hennen, Stephanie
Preis, Philip
Schmitt, Nina-Katharina
Peters, Lucas
Schrage, Ramona
Vermeiren, Celine
Gillard, Michel
Mohr, Klaus
Gomeza, Jesus
Kostenis, Evi
description 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 the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into the pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as a dualistic uracil nucleotide/cysteinyl leukotriene receptor and by others as inactive toward these stimuli altogether. Whereas regulation of central nervous system 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 be accomplished with neither the coapplication of both ligand classes nor the exogenous transfection of partner receptors nucleotide purinergic G protein–coupled receptor, cysteinyl leukotriene 1, to reconstitute the elusive pharmacology. Moreover, our study does not support the 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 an orchestrator of central nervous system functions, they challenge the utility of the proposed (ant)agonists as tools to imply direct contribution of GPR17 in complex biologic settings.
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It follows that the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into the pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as a dualistic uracil nucleotide/cysteinyl leukotriene receptor and by others as inactive toward these stimuli altogether. Whereas regulation of central nervous system 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. 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subjects Adenosine - analogs & derivatives
Adenosine - pharmacology
Adenosine Monophosphate - analogs & derivatives
Adenosine Monophosphate - pharmacology
Animals
Cell Membrane - drug effects
Cell Membrane - metabolism
CHO Cells
Cricetinae
Cricetulus
Cysteine - pharmacology
HEK293 Cells
Humans
Leukotrienes - pharmacology
Ligands
Mice
Nerve Tissue Proteins - metabolism
Rats
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - drug effects
Small Molecule Libraries - pharmacology
Uracil Nucleotides - pharmacology
title The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes
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