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  • br Materials and methods br Results and discussion

    2019-11-11


    Materials and methods
    Results and discussion
    Conclusions Data about the ability of non-conventional ligands to operate class-A GPCRs have been accumulating. Specifically, increasing evidence indicates that oxysterols, oxidized derivatives of cholesterol, are involved in many activities that are not strictly associated with cholesterol metabolism and may act as emergency signaling molecules in neurodegenerative disorders, including demyelinating diseases [29]. Different research groups, ours included, have recently described the ability of oxysterols to bind not only to their canonical receptors (the oxysterol receptors LXRs), but to also show a ‘promiscuous’ behavior in activating, in a specific but not selective manner, other receptors, namely selected GPCRs. In particular, the three investigated GPCRs show a common binding space, in which oxysterols can place themselves with different local arrangements. This evidence may explain the different potency of the same oxysterol on each individual receptor. Our data suggest that each of these three class-A GPCRs shows higher sensitivity to a specific oxysterol and a different activation threshold which potentially differentiates the final biological effect of these compounds, depending on the site of production, their concentration, specific spatio-temporal features and the typical receptor APETx2 mg pattern of the targeted cell/tissue. Besides being common molecular targets of oxysterols, EBI2, CXCR2 and GPR17 are phylogenetically related to each other and also participate in CNS inflammatory responses. Notably, these three receptors respond to other already characterized independent families of endogenous ligands, which are known to participate to the onset and/or resolution of the inflammatory reaction. It is not a chance that oxysterols are also produced locally at APETx2 mg high concentrations under distinct pathological conditions, such as ischemic, inflammatory, neurodegenerative and neoplastic diseases. Of interest, UDPglucose, one of the canonical ligands of GPR17, increases the affinity or potency of 22R-, 7α- and 27-hydroxycholesterol, suggesting that conventional and non-conventional ligands may work together under danger conditions. We thus hypothesize that oxysterols may act as immediate emergency signals alerting specific GPCRs, likely to ‘prime’ towards their conventional ligands; alternatively, oxysterols may act transversally to ‘synchronize’ some GPCRs and induce them to act together, maybe via the formation of homomers or heteromers mediating distinct biological effects. Such a transversal role for oxysterols challenges a classical pharmacological paradigm according to which a family of endogenous ligands specifically interacts with just one single class-A GPCR. According to our data, CXCR2 and GPR17 are operated by oxysterols as promiscuous ligands, making this class of ligands a ‘fil rouge’ linking oxidative stress, inflammation and neurodegeneration. Future studies will clarify the extent of oxysterol involvement in class-A GPCR inter-operability and the pathophysiological significance of this common transversal receptor activation process.
    Acknowledgments Authors are deeply grateful to the Italian Multiple Sclerosis Foundation (FISM) for the financial support (Project N. 2013/R1 to MPA).
    EBV Infection Epstein–Barr virus (EBV, human herpesvirus 4) was discovered 50 years ago, when Epstein, Achong, and Barr used electron microscopy to identify viral particles in Burkitt\'s lymphoma cells. It belongs to the lymphocryptovirus (LCV) genus of the gammaherpesvirus subfamily (Fig. 1A). The EBV genome, which consists of a linear, double-stranded DNA molecule that encodes close to 100 viral genes, is enclosed in a nuclear capsid surrounded by a protein tegument, which in turn, is surrounded by a glycoprotein-coated viral envelope. The glycoproteins are important for virus tropism, host selectivity, and infection.