A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights
Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is...
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Veröffentlicht in: | Cellular signalling 2016-06, Vol.28 (6), p.631-642 |
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creator | Parravicini, Chiara Daniele, Simona Palazzolo, Luca Trincavelli, Maria Letizia Martini, Claudia Zaratin, Paola Primi, Roberto Coppolino, Giusy Gianazza, Elisabetta Abbracchio, Maria P. Eberini, Ivano |
description | Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is likely to unveil new pathophysiological roles and novel emerging pharmacological properties for some of these GPCRs, including GPR17. This receptor shares structural, phylogenetic and functional properties with some chemokine receptors, CXCRs. Both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCR ligands have been demonstrated to have a role in orchestrating inflammatory responses and oligodendrocyte precursor cell differentiation to myelinating cells in acute and chronic diseases of the central nervous system. Here, by combining in silico modelling data with in vitro validation in (i) a classical reference pharmacological assay for GPCR activity and (ii) a model of maturation of primary oligodendrocyte precursor cells, we demonstrate that GPR17 can be activated by SDF-1, a ligand of chemokine receptors CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism. We also demonstrate that cangrelor, a GPR17 orthosteric antagonist, can block the SDF-1-mediated activation of GPR17 in a concentration-dependent manner. The ability of GPR17 to respond to different classes of GPCR ligands suggests that this receptor modifies its function depending on the extracellular mileu changes occurring under specific pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an inflammatory/immune component.
[Display omitted]
•GPR17 is a promiscuous class-A GPCR operated by different ligand families.•The chemokine receptor ligand SDF-1 interacts with GPR17 via an extended network.•SDF-1 binding to GPR17 activates intracellular heterotrimeric Gi protein pathway.•GPR17 activation by SDF-1 promotes maturation of oligodendrocyte precursor cells.•Cangrelor competitively antagonizes SDF-1 activation of GPR17. |
doi_str_mv | 10.1016/j.cellsig.2016.03.001 |
format | Article |
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[Display omitted]
•GPR17 is a promiscuous class-A GPCR operated by different ligand families.•The chemokine receptor ligand SDF-1 interacts with GPR17 via an extended network.•SDF-1 binding to GPR17 activates intracellular heterotrimeric Gi protein pathway.•GPR17 activation by SDF-1 promotes maturation of oligodendrocyte precursor cells.•Cangrelor competitively antagonizes SDF-1 activation of GPR17.</description><identifier>ISSN: 0898-6568</identifier><identifier>EISSN: 1873-3913</identifier><identifier>DOI: 10.1016/j.cellsig.2016.03.001</identifier><identifier>PMID: 26971834</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Activation ; Adenosine Monophosphate - analogs & derivatives ; Adenosine Monophosphate - chemistry ; Animals ; Cells, Cultured ; Central nervous system ; Chemokine CXCL12 - chemistry ; Chemokine CXCL12 - metabolism ; Chemokine receptors ; Class-A GPCRs ; Demyelinating diseases ; GPR17 ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Neuroinflammation ; Pharmacology ; Precursors ; Protein Binding ; Rats, Sprague-Dawley ; Receptors ; Receptors, G-Protein-Coupled - chemistry ; Receptors, G-Protein-Coupled - metabolism ; Recognition ; SDF-1</subject><ispartof>Cellular signalling, 2016-06, Vol.28 (6), p.631-642</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-d66ca8dd5fa769695aa52e1177fc49a514b89668830b924cf719bf507ba709f13</citedby><cites>FETCH-LOGICAL-c445t-d66ca8dd5fa769695aa52e1177fc49a514b89668830b924cf719bf507ba709f13</cites><orcidid>0000-0002-4115-0094 ; 0000-0001-5521-3829</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cellsig.2016.03.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26971834$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parravicini, Chiara</creatorcontrib><creatorcontrib>Daniele, Simona</creatorcontrib><creatorcontrib>Palazzolo, Luca</creatorcontrib><creatorcontrib>Trincavelli, Maria Letizia</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><creatorcontrib>Zaratin, Paola</creatorcontrib><creatorcontrib>Primi, Roberto</creatorcontrib><creatorcontrib>Coppolino, Giusy</creatorcontrib><creatorcontrib>Gianazza, Elisabetta</creatorcontrib><creatorcontrib>Abbracchio, Maria P.</creatorcontrib><creatorcontrib>Eberini, Ivano</creatorcontrib><title>A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights</title><title>Cellular signalling</title><addtitle>Cell Signal</addtitle><description>Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is likely to unveil new pathophysiological roles and novel emerging pharmacological properties for some of these GPCRs, including GPR17. This receptor shares structural, phylogenetic and functional properties with some chemokine receptors, CXCRs. Both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCR ligands have been demonstrated to have a role in orchestrating inflammatory responses and oligodendrocyte precursor cell differentiation to myelinating cells in acute and chronic diseases of the central nervous system. Here, by combining in silico modelling data with in vitro validation in (i) a classical reference pharmacological assay for GPCR activity and (ii) a model of maturation of primary oligodendrocyte precursor cells, we demonstrate that GPR17 can be activated by SDF-1, a ligand of chemokine receptors CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism. We also demonstrate that cangrelor, a GPR17 orthosteric antagonist, can block the SDF-1-mediated activation of GPR17 in a concentration-dependent manner. The ability of GPR17 to respond to different classes of GPCR ligands suggests that this receptor modifies its function depending on the extracellular mileu changes occurring under specific pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an inflammatory/immune component.
[Display omitted]
•GPR17 is a promiscuous class-A GPCR operated by different ligand families.•The chemokine receptor ligand SDF-1 interacts with GPR17 via an extended network.•SDF-1 binding to GPR17 activates intracellular heterotrimeric Gi protein pathway.•GPR17 activation by SDF-1 promotes maturation of oligodendrocyte precursor cells.•Cangrelor competitively antagonizes SDF-1 activation of GPR17.</description><subject>Activation</subject><subject>Adenosine Monophosphate - analogs & derivatives</subject><subject>Adenosine Monophosphate - chemistry</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Central nervous system</subject><subject>Chemokine CXCL12 - chemistry</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>Chemokine receptors</subject><subject>Class-A GPCRs</subject><subject>Demyelinating diseases</subject><subject>GPR17</subject><subject>Ligands</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Neuroinflammation</subject><subject>Pharmacology</subject><subject>Precursors</subject><subject>Protein Binding</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors</subject><subject>Receptors, G-Protein-Coupled - chemistry</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Recognition</subject><subject>SDF-1</subject><issn>0898-6568</issn><issn>1873-3913</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtP3DAURq2qqAxDf0IrL7tJ6hvHr26qES1QCQTisbYc5wY8ymMaJ1T8ezyaKdtZXV3p3Md3CPkCLAcG8vs699i2MTzlRWpzxnPG4ANZgFY84wb4R7Jg2uhMCqmPyUmM6wQIJotP5LiQRoHm5YLcrOhmHLoQ_TzMkY7oh6c-TGHoaYf-2fUhdrTC6R9iTy9u70BR19f0_td5Bj_o9dCin1s30tCnV56neEqOGtdG_LyvS_J4_vvh7DK7urn4c7a6ynxZiimrpfRO17VonJJGGuGcKBBAqcaXxgkoK22k1JqzyhSlbxSYqhFMVU4x0wBfkm-7ven7vzPGyW4zJCOuxxTEggbJCsOZOIwqZbQuSlkmVOxQPw4xjtjYzRg6N75aYHar3a7tXrvdareM22Q1zX3dn5irDuv3qf-eE_BzB2By8hJwtNEH7D3WISmfbD2EAyfeAMfSlGM</recordid><startdate>201606</startdate><enddate>201606</enddate><creator>Parravicini, Chiara</creator><creator>Daniele, Simona</creator><creator>Palazzolo, Luca</creator><creator>Trincavelli, Maria Letizia</creator><creator>Martini, Claudia</creator><creator>Zaratin, Paola</creator><creator>Primi, Roberto</creator><creator>Coppolino, Giusy</creator><creator>Gianazza, Elisabetta</creator><creator>Abbracchio, Maria P.</creator><creator>Eberini, Ivano</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><scope>7X8</scope><scope>7U5</scope><scope>8FD</scope><scope>L7M</scope><orcidid>https://orcid.org/0000-0002-4115-0094</orcidid><orcidid>https://orcid.org/0000-0001-5521-3829</orcidid></search><sort><creationdate>201606</creationdate><title>A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights</title><author>Parravicini, Chiara ; Daniele, Simona ; Palazzolo, Luca ; Trincavelli, Maria Letizia ; Martini, Claudia ; Zaratin, Paola ; Primi, Roberto ; Coppolino, Giusy ; Gianazza, Elisabetta ; Abbracchio, Maria P. ; Eberini, Ivano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-d66ca8dd5fa769695aa52e1177fc49a514b89668830b924cf719bf507ba709f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Activation</topic><topic>Adenosine Monophosphate - analogs & derivatives</topic><topic>Adenosine Monophosphate - chemistry</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Central nervous system</topic><topic>Chemokine CXCL12 - chemistry</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>Chemokine receptors</topic><topic>Class-A GPCRs</topic><topic>Demyelinating diseases</topic><topic>GPR17</topic><topic>Ligands</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>Neuroinflammation</topic><topic>Pharmacology</topic><topic>Precursors</topic><topic>Protein Binding</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors</topic><topic>Receptors, G-Protein-Coupled - chemistry</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Recognition</topic><topic>SDF-1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parravicini, Chiara</creatorcontrib><creatorcontrib>Daniele, Simona</creatorcontrib><creatorcontrib>Palazzolo, Luca</creatorcontrib><creatorcontrib>Trincavelli, Maria Letizia</creatorcontrib><creatorcontrib>Martini, Claudia</creatorcontrib><creatorcontrib>Zaratin, Paola</creatorcontrib><creatorcontrib>Primi, Roberto</creatorcontrib><creatorcontrib>Coppolino, Giusy</creatorcontrib><creatorcontrib>Gianazza, Elisabetta</creatorcontrib><creatorcontrib>Abbracchio, Maria P.</creatorcontrib><creatorcontrib>Eberini, Ivano</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Technology Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Cellular signalling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parravicini, Chiara</au><au>Daniele, Simona</au><au>Palazzolo, Luca</au><au>Trincavelli, Maria Letizia</au><au>Martini, Claudia</au><au>Zaratin, Paola</au><au>Primi, Roberto</au><au>Coppolino, Giusy</au><au>Gianazza, Elisabetta</au><au>Abbracchio, Maria P.</au><au>Eberini, Ivano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights</atitle><jtitle>Cellular signalling</jtitle><addtitle>Cell Signal</addtitle><date>2016-06</date><risdate>2016</risdate><volume>28</volume><issue>6</issue><spage>631</spage><epage>642</epage><pages>631-642</pages><issn>0898-6568</issn><eissn>1873-3913</eissn><abstract>Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is likely to unveil new pathophysiological roles and novel emerging pharmacological properties for some of these GPCRs, including GPR17. This receptor shares structural, phylogenetic and functional properties with some chemokine receptors, CXCRs. Both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCR ligands have been demonstrated to have a role in orchestrating inflammatory responses and oligodendrocyte precursor cell differentiation to myelinating cells in acute and chronic diseases of the central nervous system. Here, by combining in silico modelling data with in vitro validation in (i) a classical reference pharmacological assay for GPCR activity and (ii) a model of maturation of primary oligodendrocyte precursor cells, we demonstrate that GPR17 can be activated by SDF-1, a ligand of chemokine receptors CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism. We also demonstrate that cangrelor, a GPR17 orthosteric antagonist, can block the SDF-1-mediated activation of GPR17 in a concentration-dependent manner. The ability of GPR17 to respond to different classes of GPCR ligands suggests that this receptor modifies its function depending on the extracellular mileu changes occurring under specific pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an inflammatory/immune component.
[Display omitted]
•GPR17 is a promiscuous class-A GPCR operated by different ligand families.•The chemokine receptor ligand SDF-1 interacts with GPR17 via an extended network.•SDF-1 binding to GPR17 activates intracellular heterotrimeric Gi protein pathway.•GPR17 activation by SDF-1 promotes maturation of oligodendrocyte precursor cells.•Cangrelor competitively antagonizes SDF-1 activation of GPR17.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>26971834</pmid><doi>10.1016/j.cellsig.2016.03.001</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4115-0094</orcidid><orcidid>https://orcid.org/0000-0001-5521-3829</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Activation Adenosine Monophosphate - analogs & derivatives Adenosine Monophosphate - chemistry Animals Cells, Cultured Central nervous system Chemokine CXCL12 - chemistry Chemokine CXCL12 - metabolism Chemokine receptors Class-A GPCRs Demyelinating diseases GPR17 Ligands Molecular Docking Simulation Molecular Dynamics Simulation Neuroinflammation Pharmacology Precursors Protein Binding Rats, Sprague-Dawley Receptors Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - metabolism Recognition SDF-1 |
title | A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights |
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