激活剂(遗传学)
孤儿受体
受体
内生
生物
生物化学
化学
细胞生物学
转录因子
基因
作者
Anthony W. Harrington,Changlu Liu,Naomi Phillips,Diane Nepomuceno,Chester Kuei,Joseph Chang,Weixuan Chen,Steven W. Sutton,Daniel O’Malley,Ly Pham,Xiang Yao,Siquan Sun,Pascal Bonaventure
摘要
GPR17 is an orphan receptor involved in the process of myelination due to its ability to inhibit the maturation of oligodendrocyte progenitor cells into myelinating oligodendrocytes. Despite multiple claims that the biological ligand has been identified, it remains an orphan receptor.Seventy-seven oxysterols were screened in a cell-free [35 S]GTPgS binding assay using membranes from cells expressing GPR17. The positive hits were characterised using cAMP, IP1, and calcium mobilisation assays, with results confirmed in rat primary oligodendrocytes. Rat and pig brain extracts were separated by HPLC chromatography and endogenous activator(s) were identified in receptor activation assays. Gene expression studies of GPR17 and CYP46A1, the enzymes responsible for the conversion of cholesterol into specific oxysterols, were performed using quantitative real time PCR.Five oxysterols were able to stimulate GPR17 activity, including the brain cholesterol, 24(S)-hydroxycholesterol (24S-HC). A specific brain fraction from rat and pig extracts containing 24S-HC activates GPR17 in vitro. Expression of Gpr17 during mouse brain development correlates with the expression of Cyp46a1 and the levels of 24S-HC itself. Other active oxysterols have low brain concentrations below effective ranges.Oxysterols, including but not limited to 24S-HC, could be physiological activators for GPR17 and thus potentially regulate OPC differentiation and myelination through activation of the receptor.
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