Xiao Ai Ying, Wang Xue Qing, Yang Aizhen, Yu Shan Ping
Department of Neurology, Box 811, School of Medicine, Washington University, St Louis, MO 63110, USA.
Brain Res. 2002 Nov 15;955(1-2):253-9. doi: 10.1016/s0006-8993(02)03472-8.
Dysfunction of the Na(+),K(+)-ATPase (Na(+),K(+)-pump), due to reduced energy supply or increased endogenous ouabain-like inhibitors, likely occurs under pathological conditions in the central nervous system. In cultured mouse cortical neurons, we examined the hypothesis that a mild non-toxic inhibition of the Na(+),K(+)-ATPase could synergistically sensitize the vulnerability of neurons to normally non-lethal apoptotic signals. Ouabain at a low concentration of 0.1 microM slightly lessened the Na(+),K(+)-pump activity measured as an ouabain-sensitive current, yet did not affect K(+) homeostasis and viability of cortical neurons. Co-exposure to 0.1 microM ouabain plus non-lethal C(2)-ceramide (5 microM) or beta-amyloid 1-42 (5 microM), however, induced marked intracellular K(+) loss, caspase-3 cleavage, DNA laddering, and synergistically triggered neuronal death. The caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) predominantly blocked the caspase activation and neuronal death. These results suggest that slight impairment of Na(+),K(+)-pump activity may amplify the disruption of K(+) homeostasis in the presence of a non-lethal apoptotic insult, leading to activation of apoptotic cascade and substantial neuronal injury.
由于能量供应减少或内源性哇巴因样抑制剂增加，钠钾ATP酶（钠钾泵）功能障碍很可能在中枢神经系统的病理条件下发生。在培养的小鼠皮层神经元中，我们检验了这样一种假说，即对钠钾ATP酶进行轻度无毒抑制可能会协同增加神经元对通常非致命性凋亡信号的易损性。低浓度（0.1微摩尔）的哇巴因略微降低了以哇巴因敏感电流衡量的钠钾泵活性，但不影响皮层神经元的钾稳态和活力。然而，同时暴露于0.1微摩尔哇巴因加非致命性的C2-神经酰胺（5微摩尔）或β-淀粉样蛋白1-42（5微摩尔）会导致明显的细胞内钾流失、半胱天冬酶-3裂解、DNA梯状条带形成，并协同引发神经元死亡。半胱天冬酶抑制剂Z-缬氨酸-丙氨酸-天冬氨酸（OMe）-氟甲基酮（Z-VAD-FMK）主要阻断了半胱天冬酶的激活和神经元死亡。这些结果表明，在存在非致命性凋亡刺激的情况下，钠钾泵活性的轻微损害可能会放大钾稳态的破坏，导致凋亡级联反应激活和严重的神经元损伤。
