title: A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights.
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.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: chiara.parravicini@unimi.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Parravicini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: simona.daniele@for.unipi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: luca.palazzolo@guest.unimi.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Palazzolo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: ltrincavelli@farm.unipi.it.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. Electronic address: claudia.martini@unipi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Fondazione Italiana Sclerosi Multipla, Via Operai 40, 16149 Genova, Italy. Electronic address: paola.zaratin@aism.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Zaratin
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: roberto.primi@guest.unimi.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Primi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: giusy.coppolino@unimi.it.
authors.forename: Giusy
authors.initials: G
authors.lastname: Coppolino
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: elisabetta.gianazza@unimi.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gianazza
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: mariapia.abbracchio@unimi.it.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy; Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Via Gian Battista Grassi 74, 20157 Milano, Italy. Electronic address: ivano.eberini@unimi.it.
authors.forename: Ivano
authors.initials: I
authors.lastname: Eberini
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C121670:GPR17 protein, human; D043562:Receptors, G-Protein-Coupled; D000249:Adenosine Monophosphate; C117446:cangrelor
keywords: Chemokine receptors; Class-A GPCRs; Demyelinating diseases; GPR17; Neuroinflammation; SDF-1