Divi Department of Neuroscience, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy.
Glia. 2013 Jul;61(7):1155-71. doi: 10.1002/glia.22506. Epub 2013 May 2.
In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K(+) currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G-protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K(+) currents. Specifically, receptor stimulation by its agonist UDP-glucose enhances delayed rectifier K(+) currents without affecting transient K(+) conductances. This effect was observed in a subpopulation of OPCs and immature pre-OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP-glucose on K(+) currents is concentration-dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K(+) channel blocker tetraethyl-ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K(+) currents is responsible for GPR17-induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post-traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma.
在发育和成熟的中枢神经系统中，表达 NG2 的细胞组成了一个具有增殖能力的少突胶质前体细胞（OPC）群体，这些细胞分化为成熟的髓鞘形成少突胶质细胞（OLG）。OPC 还具有高迁移性，并在受到损伤时迁移到损伤区域以支持髓鞘再生。OPC 中的 K+电流在分化过程中受到发育调控。然而，在少突胶质细胞谱系的不同阶段调节这些电流的机制还知之甚少。在这里，我们发现在培养的原代 OPC 中，嘌呤能 G 蛋白偶联受体 GPR17，最近作为少突胶质发生的关键因子出现，对 K+电流起着至关重要的调节作用。具体来说，其激动剂 UDP-葡萄糖对受体的刺激增强了延迟整流型 K+电流，而不影响瞬时 K+电导。这种效应在 OPC 的一个亚群和不成熟的前 OLG 中观察到，而在成熟的 OLG 中则不存在，这与 GPR17 的表达一致，GPR17 的表达在少突胶质细胞分化的中期达到高峰，随后下调以允许终末成熟。UDP-葡萄糖对 K+电流的影响呈浓度依赖性，被 GPR17 拮抗剂 MRS2179 和 cangrelor 阻断，并且对 K+通道阻断剂四乙铵敏感，四乙铵也抑制少突胶质细胞成熟。我们提出，K+电流的刺激是 GPR17 诱导的少突胶质细胞分化的原因。此外，我们首次证明，GPR17 的激活刺激 OPC 迁移，表明该受体在脑损伤后具有重要作用。我们的数据表明，GPR17 的激活可能代表了一种在脱髓鞘条件下（如多发性硬化症、中风和脑外伤）增强 OPC 创伤后反应的策略。
