Lecca, R. recycled to the cell surface. Furthermore, internalized GPR17 displayed a co-localization with the marker of the short loop recycling endosomes, Rab4, while showing very minor co-localization with the long loop recycling marker, Rab11. Our results provide the first data around the Rabbit Polyclonal to CACNG7 agonist-induced trafficking of native GPR17 in oligodendroglial cells and may have implications for both physiological and pathological myelination. UDP and UDP-glucose) and arachidonic acid-derived cysLTs (LTD4 and LTE4). The physiological role of GPR17 has been deeply investigated in both and systems, and a number of studies have revealed its crucial role in oligodendrocyte precursor cell (OPC) differentiation (2, 7C11). Receptor expression, almost absent in early Jujuboside B OPCs, gradually increases in more mature precursors, reaches a plateau in immature/pre-oligodendrocytes, and then gradually decreases during terminal differentiation. In line with these findings, GPR17 is usually co-expressed with the early oligodendrocyte marker NG2 and markers of pre/immature oligodendrocyte phenotype (such as O4 and DM-20) but is usually down-regulated in cells expressing myelin proteins such as myelin basic protein, which is usually highly synthesized in fully mature cells (7, Jujuboside B 10, 11). Consistent with the role of GPR17 in oligodendrocyte ontogenesis, its activation by natural agonists promotes OPC differentiation under physiological conditions (2, 10). In contrast, the inhibition of GPR17 expression causes an impairment in oligodendrocyte differentiation and myelination in both (7) and systems (10). Altogether, these studies indicate that GPR17 is an integral signaling component controlling oligodendrocyte ontogenesis and suggest that the appropriate activation and deactivation of GPR17 are Jujuboside B crucial actions in OPC maturation. As it has been reported for many GPCRs, after ligand binding, GPR17 may undergo endocytosis and subsequent sorting into lysosomes for degradation and/or into recycling endosomes for re-incorporation into the plasma membrane. The balance of this dynamic intracellular trafficking is usually physiologically relevant because it modulates receptor levels at the cell surface. This process has important implications for the activation or silencing of GPR17-signaling pathway(s), and in turn, for OPC differentiation (12C16). It may even be hypothesized that GPR17 endocytosis may represent a key event necessary to allow OPCs to proceed to myelination. A similar process has been associated with the specification of other cell lineages, where the down-regulation of membrane receptors has been proposed to be necessary to allow cells to proceed toward terminal differentiation (17). Interestingly, the abnormal up-regulation of GPR17 has been associated with defective myelination during development and with multiple sclerosis (7). Thus, the characterization of the mechanisms involved in the expression of GPR17 in the plasma membrane may help us to better understand the molecular mechanisms of the contribution of GPR17 to oligodendrogenesis and may set the background for interpreting the consequences of GPR17 dysfunction in disease. At present, however, there are Jujuboside B very few studies available on the trafficking of GPR17 both under basal conditions and upon activation. In 1321N1 cells heterologously expressing hGPR17, it has been demonstrated that this GPR17 agonists UDP-glucose and LTD4 determine receptor desensitization/re-sensitization (6). On the other hand, a previous study has failed to demonstrate the direct activation of GPR17 by agonists, proposing how the receptor may work as a exclusively.