GPR17 receptor-mediated intracellular pathway and regulatory mechanisms: studies for novel therapies

The P2Y-like G-protein-coupled receptor (GPCR) GPR17 is structurally and phylogenetically related to the already known P2Y receptors for extracellular nucleotides and the cysteinyl leukotriene 1 receptor and cysteinyl leukotriene 2 receptor for arachidonic acid-derived cysteinyl-leukotrienes. This receptor seems to act as both a classical ligand-activated GPCR, responding to both uracil nucleotides and cysteinyl-leukotrienes and as a direct, negative regulator of the cysteinyl leukotriene 1 receptor. In intact brain, GPR17 is normally present on neurons and on a subset of oligodendrocyte precursor cells. In pathological conditions, this receptor plays a role in inducing early necrotic death inside the lesion, but also participates in the subsequent remodeling and repair of the lesioned area, occurring in the days and weeks after injury. In order to shed light on GPR17 receptor-mediated intracellular pathway and regulatory mechanisms, during my PhD I investigated: i) Pharmacological profile of new GPR17 ligands ii) Role of GPR17 in neuron survival and differentiation iii) Phenotypic changes and signaling pathway of GPR17-expressing neural precursor cells during oligodendrocyte differentiation iv) Agonist-induced desensitization/resensitization of GPR17 My PhD work led to the identification of new promising GPR17 ligands, which could represent a starting point for novel therapies in neurodegenerative diseases. Moreover, the results demonstrate that GPR17 plays an important role in neuron and oligodendrocyte differentiation. In particular, GPR17 receptor desensitization and removal from the cell membrane, with subsequent internalization and degradation, may be a starting event in the control of GPR17 levels necessary to allow oligodendrocytes to proceed to myelination.