Crystal structure and functional characterization of the GPR17 receptor, a novel pharmacological target for remyelination therapy in multiple sclerosis

GPR17 is a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g. UDP-glucose and LTD4) . It is highly expressed on oligodendroglial precursors (OPCs), the myelin producing cells. Recent studies investigated on GPR17 as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS)2. The dissection of the molecular pathways underlying the pro-myelinating activity of GPR17 represents a crucial goal for understanding some of pathogenic aspects of MS and for the development of innovative, reparative-based therapy. This objective would dramatically benefit from the availability of an experimental crystal structure of GPR17. The overall goal of this project is to obtain a high-resolution crystal of GPR17 that, together with in silico molecular modelling studies, will allow to elucidate the structure of the protein and define, at molecular level, the structural elements and interactions that dictate receptor activation and agonist/antagonist activities. Among allosteric ligands of several G protein coupled receptors, sodium ions are emerging as deep modulators3. Nevertheless, the effect of sodium on GPR17 has not been investigated yet. On this basis, the aim of this work is thus to investigate sodium modulation on GPR17 ligand binding and functionality. To this purpose, different sodium concentrations were tested in functional assays using wild-type GPR17 and selected receptor variants.