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 |
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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. |
doi_str_mv | 10.1124/mol.116.107904 |
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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. 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.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.116.107904</identifier><identifier>PMID: 28254957</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>Molecular pharmacology, 2017-05, Vol.91 (5), p.518-532</ispartof><rights>2017 American Society for Pharmacology and Experimental Therapeutics</rights><rights>Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-80764c6dfc104bf959c7b903b6684868b6d195cbe0c45539bc7ca88d1ed205553</citedby><cites>FETCH-LOGICAL-c384t-80764c6dfc104bf959c7b903b6684868b6d195cbe0c45539bc7ca88d1ed205553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28254957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Simon, Katharina</creatorcontrib><creatorcontrib>Merten, Nicole</creatorcontrib><creatorcontrib>Schröder, Ralf</creatorcontrib><creatorcontrib>Hennen, Stephanie</creatorcontrib><creatorcontrib>Preis, Philip</creatorcontrib><creatorcontrib>Schmitt, Nina-Katharina</creatorcontrib><creatorcontrib>Peters, Lucas</creatorcontrib><creatorcontrib>Schrage, Ramona</creatorcontrib><creatorcontrib>Vermeiren, Celine</creatorcontrib><creatorcontrib>Gillard, Michel</creatorcontrib><creatorcontrib>Mohr, Klaus</creatorcontrib><creatorcontrib>Gomeza, Jesus</creatorcontrib><creatorcontrib>Kostenis, Evi</creatorcontrib><title>The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><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.</description><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - pharmacology</subject><subject>Adenosine Monophosphate - analogs & derivatives</subject><subject>Adenosine Monophosphate - pharmacology</subject><subject>Animals</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cysteine - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Leukotrienes - pharmacology</subject><subject>Ligands</subject><subject>Mice</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Rats</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Uracil Nucleotides - pharmacology</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kFFLwzAUhYMobk5ffZT8gdakS9LkUYbOwXAyNhBfSpvcsmjXlKQb7N8bqfrm0z1czjnc-yF0S0lKacbu966JQqSU5IqwMzSmPKMJoZSeozEhmUik4m8jdBXCByGUcUku0SiTGWeK52P0vtkBXvluV7Z4DRq63nk8f13THC8C3rYeQufaYI-Ae4e3vtS2wS8H3YDrrYGAy9bg2Sn0YNtTg5dw-HS9t9BCuEYXddkEuPmZE7R9etzMnpPlar6YPSwTPZWsTyTJBdPC1JoSVtWKK51XikwrISSTQlbCUMV1BUQzzqeq0rkupTQUTEZ43ExQOvRq70LwUBedt_vSnwpKim9IRYQUhSgGSDFwNwS6Q7UH82f_pRINcjBAPPtowRdBx5c0GOtB94Vx9r_uL_CUdbA</recordid><startdate>201705</startdate><enddate>201705</enddate><creator>Simon, Katharina</creator><creator>Merten, Nicole</creator><creator>Schröder, Ralf</creator><creator>Hennen, Stephanie</creator><creator>Preis, Philip</creator><creator>Schmitt, Nina-Katharina</creator><creator>Peters, Lucas</creator><creator>Schrage, Ramona</creator><creator>Vermeiren, Celine</creator><creator>Gillard, Michel</creator><creator>Mohr, Klaus</creator><creator>Gomeza, Jesus</creator><creator>Kostenis, Evi</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>201705</creationdate><title>The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-80764c6dfc104bf959c7b903b6684868b6d195cbe0c45539bc7ca88d1ed205553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adenosine - analogs & derivatives</topic><topic>Adenosine - pharmacology</topic><topic>Adenosine Monophosphate - analogs & derivatives</topic><topic>Adenosine Monophosphate - pharmacology</topic><topic>Animals</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cysteine - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Leukotrienes - pharmacology</topic><topic>Ligands</topic><topic>Mice</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Rats</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Uracil Nucleotides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Simon, Katharina</creatorcontrib><creatorcontrib>Merten, Nicole</creatorcontrib><creatorcontrib>Schröder, Ralf</creatorcontrib><creatorcontrib>Hennen, Stephanie</creatorcontrib><creatorcontrib>Preis, Philip</creatorcontrib><creatorcontrib>Schmitt, Nina-Katharina</creatorcontrib><creatorcontrib>Peters, Lucas</creatorcontrib><creatorcontrib>Schrage, Ramona</creatorcontrib><creatorcontrib>Vermeiren, Celine</creatorcontrib><creatorcontrib>Gillard, Michel</creatorcontrib><creatorcontrib>Mohr, Klaus</creatorcontrib><creatorcontrib>Gomeza, Jesus</creatorcontrib><creatorcontrib>Kostenis, Evi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Simon, Katharina</au><au>Merten, Nicole</au><au>Schröder, Ralf</au><au>Hennen, Stephanie</au><au>Preis, Philip</au><au>Schmitt, Nina-Katharina</au><au>Peters, Lucas</au><au>Schrage, Ramona</au><au>Vermeiren, Celine</au><au>Gillard, Michel</au><au>Mohr, Klaus</au><au>Gomeza, Jesus</au><au>Kostenis, Evi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>2017-05</date><risdate>2017</risdate><volume>91</volume><issue>5</issue><spage>518</spage><epage>532</epage><pages>518-532</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28254957</pmid><doi>10.1124/mol.116.107904</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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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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