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
Hauptverfasser: Parravicini, Chiara, Daniele, Simona, Palazzolo, Luca, Trincavelli, Maria Letizia, Martini, Claudia, Zaratin, Paola, Primi, Roberto, Coppolino, Giusy, Gianazza, Elisabetta, Abbracchio, Maria P., Eberini, Ivano
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container_end_page 642
container_issue 6
container_start_page 631
container_title Cellular signalling
container_volume 28
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
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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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