| Autor: |
Daniele S; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy., Saporiti S; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Capaldi S; Dipartimento di Biotecnologie, Università degli Studi di Verona, Strada Le Grazie 15, 37134 Verona, Italy., Pietrobono D; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy., Russo L; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy., Guerrini U; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Laurenzi T; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Ataie Kachoie E; Dipartimento di Biotecnologie, Università degli Studi di Verona, Strada Le Grazie 15, 37134 Verona, Italy., Palazzolo L; Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Russo V; Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology Scientific, Institute San Raffaele, 20132 Milan, Italy., Abbracchio MP; Laboratorio di Farmacologia Molecolare e Cellulare Della Trasmissione Purinergica, Dipartimento di Scienze Farmaceutiche, Università Degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Eberini I; Dipartimento di Scienze Farmacologiche e Biomolecolari & Data Science Research Center (DSRC), Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy., Trincavelli ML; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. |
| Abstrakt: |
GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions. Herein, the chemokine receptors CXCR2 and CXCR4 were selected to perform both in silico modelling and in vitro experiments to establish their structural and functional interactions with GPR17. The relative propensity of GPR17 and CXCR2 or CXCR4 to form homo- and hetero-dimers was assessed by homology modelling and molecular dynamics (MD) simulations, and co-immunoprecipitation and immunoenzymatic assay. The interaction between chemokine receptors and GPR17 was investigated by determining receptor-mediated modulation of intracellular cyclic adenosine monophosphate (cAMP). Our data show the GPR17 association with CXCR2 or CXCR4 and the negative regulation of these interactions by CXCR agonists or antagonists. Moreover, GPR17 and CXCR2 heterodimers can functionally influence each other. In contrast, CXCR4 can influence GPR17 functionality, but not vice versa . According to MD simulations, all the dimers reached conformational stability and negative formation energy, confirming the experimental observations. The cross-talk between these receptors could play a role in the development of the neuroinflammatory milieu associated with demyelinating events. |
