Mullershausen Florian, Craveiro Luis M, Shin Youngah, Cortes-Cros Marta, Bassilana Frederic, Osinde Maribel, Wishart William L, Guerini Danilo, Thallmair Michaela, Schwab Martin E, Sivasankaran Rajeev, Seuwen Klaus, Dev Kumlesh K
Department of G Protein-Coupled Receptors, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland.
J Neurochem. 2007 Aug;102(4):1151-61. doi: 10.1111/j.1471-4159.2007.04629.x.
Sphingosine-1-phosphate (S1P) receptors are widely expressed in the central nervous system where they are thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum of S1P receptors and the parent compound is currently in phase III clinical trials for the treatment of multiple sclerosis. Here, we aimed to identify which cell type(s) and S1P receptor(s) of the central nervous system are targeted by FTY720P. Using calcium imaging in mixed cultures from embryonic rat cortex we show that astrocytes are the major cell type responsive to FTY720P in this assay. In enriched astrocyte cultures, we detect expression of S1P1 and S1P3 receptors and demonstrate that FTY720P activates Gi protein-mediated signaling cascades. We also show that FTY720P as well as the S1P1-selective agonist SEW2871 stimulate astrocyte migration. The data indicate that FTY720P exerts its effects on astrocytes predominantly via the activation of S1P1 receptors, whereas S1P signals through both S1P1 and S1P3 receptors. We suggest that this distinct pharmacological profile of FTY720P, compared with S1P, could play a role in the therapeutic effects of FTY720 in multiple sclerosis.
鞘氨醇-1-磷酸（S1P）受体在中枢神经系统中广泛表达，人们认为它们可调节神经胶质细胞的功能。芬戈莫德/FTY720的磷酸化形式（FTY720P）对多种S1P受体具有活性，其母体化合物目前正处于治疗多发性硬化症的III期临床试验阶段。在此，我们旨在确定FTY720P作用于中枢神经系统的哪些细胞类型和S1P受体。利用胚胎大鼠皮质混合培养物中的钙成像技术，我们发现星形胶质细胞是该实验中对FTY720P有反应的主要细胞类型。在富集的星形胶质细胞培养物中，我们检测到S1P1和S1P3受体的表达，并证明FTY720P可激活Gi蛋白介导的信号级联反应。我们还表明，FTY720P以及S1P1选择性激动剂SEW2871可刺激星形胶质细胞迁移。数据表明，FTY720P主要通过激活S1P1受体对星形胶质细胞发挥作用，而S1P则通过S1P1和S1P3受体发出信号。我们认为，与S1P相比，FTY720P这种独特的药理学特性可能在FTY720治疗多发性硬化症的疗效中发挥作用。
