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Abstract：
Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A2 B adenosine receptors (A2 B Rs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K+ currents (I K ) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A2 B R expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A2 B R in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A2 B Rs in OPCs was confirmed since acute stimulation of A2 B Rs activates SphK1 by increasing its phosphorylation. Here the role of A2 B R and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A2 B Rs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.
摘要：
少突胶质细胞形成的髓鞘允许大脑中的快速突触传递。髓鞘形成过程中的损伤，或者脱髓鞘侮辱，可能导致慢性疾病，如多发性硬化症（MS）。在生理条件下,髓鞘再生是一个贯穿成人生命的持续过程,包括少突胶质祖细胞(OPCs)分化为成熟少突胶质细胞(OLs)。在病理事件期间，由于不利的环境，此过程失败。腺苷和鞘氨醇激酶/鞘氨醇1-磷酸信号轴(SphK/S1P)在髓鞘再生过程中起重要作用。值得注意的是,芬戈莫德（FTY720），最近批准用于MS治疗的鞘氨醇类似物，在OPC成熟中起着重要作用。我们最近证明，选择性刺激A2B腺苷受体（A2BRs）在体外抑制OPC分化，并降低OPC成熟所必需的电压依赖性外向K电流（IK），而特定的SphK1或SphK2抑制发挥相反的作用。在OPC分化过程中，A2BR表达增加，SphK1/2阻断可以防止这种影响。此外，OPC培养物中A2BR的选择性沉默促进成熟，有趣的是，增强S1P裂解酶的表达，负责不可逆S1P分解代谢的酶。最后,SphK1/S1P途径与OPCs中的A2BRs之间存在相互作用,因为急性刺激A2BRs通过增加SphK1的磷酸化激活。本文详细综述了A2BR和SphK/S1P信号在少突发生过程中的作用,目的是为A2BRs和S1P信号之间的相互作用提供新的思路，作为治疗脱髓鞘疾病的最终创新目标。
