IMMUNOSUPPRESSANT FK506 PROMOTES NEURITE OUTGROWTH IN CULTURES OF PC12 CELLS AND SENSORY GANGLIA
IMMUNOSUPPRESSANT FK506 PROMOTES NEURITE OUTGROWTH IN CULTURES OF PC12 CELLS AND SENSORY GANGLIA
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DOI：
10.1073/pnas.91.8.3191
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发表时间：
1994-04-12
影响因子：
11.1
通讯作者：
SNYDER, SH
中科院分区：
文献类型：
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作者：
LYONS, WE;GEORGE, EB;SNYDER, SH
免疫抑制药物FK506通过与受体蛋白FK506结合蛋白（FKBP）结合发挥作用，FK506结合蛋白（FKBP）进而可结合并调节Ca2+依赖性磷酸酶钙调神经磷酸酶和Ca2+释放通道ryanodine受体。基于我们在再生模型中的发现，即神经再生过程中FKBP的水平与生长相关蛋白GAP 43（一种调节神经突延伸的钙调神经磷酸酶底物）的水平平行，我们研究了FK506在PC12大鼠嗜铬细胞瘤细胞和大鼠感觉神经节中的作用。FK506通过增加对神经生长因子的敏感性来增强两种系统中的神经突生长。FK 506拮抗剂雷帕霉素阻断FK 506在感觉神经节中的作用，证实这些作用涉及FKBP。雷帕霉素本身刺激PC12细胞中的神经突生长。这些药物的作用是在亚纳摩尔浓度下检测到的，这表明在涉及神经变性的疾病中的治疗应用。
The immunosuppressant drug FK506 acts by binding to receptor proteins, FK506-binding proteins (FKBPs), which in turn can bind to and regulate a Ca2+-dependent phosphatase, calcineurin, and a Ca2+ release channel, the ryanodine receptor. Based on our findings in regeneration models that levels of FKBPs during neural regeneration parallel those of growth-associated protein GAP43, a calcineurin substrate that regulates neurite extension, we examined effects of FK506 in PC12 rat pheochromocytoma cells and in rat sensory ganglia. FK506 enhances neurite outgrowth in both systems by increasing sensitivity to nerve growth factor. Blockade of FK506 actions in sensory ganglia by rapamycin, an FK506 antagonist, establishes that these effects involve FKBPs. Rapamycin itself stimulates neurite outgrowth in PC12 cells. These drug effects are detected at subnanomolar concentrations, suggesting therapeutic application in diseases involving neural degeneration.