Department of Neurology, University of Toledo College of Medicine, Toledo, OH, USA.
Epilepsy Res. 2012 May;99(3):293-305. doi: 10.1016/j.eplepsyres.2011.12.011. Epub 2012 Jan 13.
Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O(2), 4h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca(2+) currents were acquired immediately after hypoxic exposure or after 48h recovery in 95% air/5% CO(2). Maximal Ca(2+) current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca(2+) currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca(2+) currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca(2+) for calcineurin activation, as nimodipine during hypoxia prevented post-hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation.
缺氧调节神经元离子通道，有时导致癫痫发作。我们评估了短暂持续缺氧（1% O(2)，4 小时）对培养的大鼠原代皮质神经元电压门控钙通道（VGCCs）的影响。高电压激活（HVA）Ca(2+)电流在缺氧暴露后或在 95%空气/5%CO(2)中的 48 小时恢复后立即获得。最大 Ca(2+)电流密度在缺氧后立即增加 1.5 倍，但在 48 小时正常氧后恢复到基线。这种增强主要是由于 L 型 VGCC 活性增加所致，因为尼莫地平不敏感的残余 Ca(2+)电流没有变化。激活的半最大电位和稳态失活不变。钙调神经磷酸酶抑制剂 FK-506（在记录电极内）或环孢素 A（在缺氧期间）防止了 HVA Ca(2+)电流在缺氧后的增加，而雷帕霉素和 okadaic 酸则没有。L 型 VGCC 是钙调神经磷酸酶激活的 Ca(2+)来源，因为在缺氧期间使用尼莫地平可防止缺氧后的增强。缺氧通过钙调神经磷酸酶短暂增强 L 型 VGCC 电流，表明存在正反馈回路，可放大神经元钙信号，可能有助于癫痫发作的发生。
