GPR17 is a class A-GPCRs operated by di erent classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. Similar to other receptors of the same class, GPR17 can associate into homo- and hetero-dimers. Recent ndings suggest its promiscuous behavior namely the possibility to be operated by ligands able to transversely interact with more than one GPCRs. In fact, both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCRn ligands have demonstrated roles in orchestrating in ammatory responses and oligodendrocyte precursor cell (OPC) di erentiation to myelinating cells in acute and chronic diseases of the CNS. Here we demonstrate that GPR17 can be activated by the chemokine stromal-derived factor-1 (SDF-1), a ligand of CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism, 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 OPCs. 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 di erent classes of GPCR ligands suggests that this receptor modi es its function depending on changes occurring in the extracellular mileu changes occurring under speci c pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an in ammatory/immune component.

GPR17 molecular modelling: interactions with non-conventional pro-inflammatory ligands / L. Palazzolo, C. Parravicini, S. Daniele, M.L. Trincavelli, C. Martini, P. Zaratin, R. Primi, G.T. Coppolino, E. Gianazza, M.P. Abbracchio, I. Eberini. ((Intervento presentato al convegno Con la nostra ricerca la SM non ci ferma tenutosi a Roma nel 2016.

GPR17 molecular modelling: interactions with non-conventional pro-inflammatory ligands

L. Palazzolo
Primo
;
C. Parravicini
Secondo
;
G.T. Coppolino;E. Gianazza;M.P. Abbracchio
Penultimo
;
I. Eberini
Ultimo
2016

Abstract

GPR17 is a class A-GPCRs operated by di erent classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. Similar to other receptors of the same class, GPR17 can associate into homo- and hetero-dimers. Recent ndings suggest its promiscuous behavior namely the possibility to be operated by ligands able to transversely interact with more than one GPCRs. In fact, both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCRn ligands have demonstrated roles in orchestrating in ammatory responses and oligodendrocyte precursor cell (OPC) di erentiation to myelinating cells in acute and chronic diseases of the CNS. Here we demonstrate that GPR17 can be activated by the chemokine stromal-derived factor-1 (SDF-1), a ligand of CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism, 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 OPCs. 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 di erent classes of GPCR ligands suggests that this receptor modi es its function depending on changes occurring in the extracellular mileu changes occurring under speci c pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an in ammatory/immune component.
27-mag-2016
Settore BIO/10 - Biochimica
Settore BIO/14 - Farmacologia
GPR17 molecular modelling: interactions with non-conventional pro-inflammatory ligands / L. Palazzolo, C. Parravicini, S. Daniele, M.L. Trincavelli, C. Martini, P. Zaratin, R. Primi, G.T. Coppolino, E. Gianazza, M.P. Abbracchio, I. Eberini. ((Intervento presentato al convegno Con la nostra ricerca la SM non ci ferma tenutosi a Roma nel 2016.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/391177
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