Slight impairment of Na+,K+-ATPase synergistically aggravates ceramide- and β-amyloid-induced apoptosis in cortical neurons
Slight impairment of Na+,K+-ATPase synergistically aggravates ceramide- and β-amyloid-induced apoptosis in cortical neurons
复制标题
DOI：
10.1016/s0006-8993(02)03472-8
复制
发表时间：
2002-11
期刊：
影响因子：
2.9
通讯作者：
A. Xiao;Xue Qing Wang;Aizhen Yang;S. Yu
中科院分区：
文献类型：
--
作者：
A. Xiao;Xue Qing Wang;Aizhen Yang;S. Yu
由于能量供应减少或内源性哇巴因样抑制剂增加，Na+，K+-ATP酶（Na+，K+-泵）的功能障碍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，我们研究了这一假设，即轻度无毒抑制Na+，K+-ATP酶可以协同敏感的脆弱性神经元正常非致死性凋亡信号。在0.1 μM的低浓度下，哇巴因轻微降低了Na+，K+泵活性，测量为哇巴因敏感电流，但不影响K+稳态和皮层神经元的活力。然而，共同暴露于0.1 μM哇巴因+非致死性C2-神经酰胺（5 μM）或β-淀粉样蛋白1-42（5 μM）可诱导明显的细胞内K+丢失、半胱天冬酶-3裂解、DNA梯状化，并协同触发神经元死亡。caspase抑制剂Z-Val-Ala-Asp（OMe）-fluoromethyl ketone（Z-VAD-FMK）主要阻断caspase激活和神经元死亡。这些结果表明，轻微损害的Na+，K+泵活性可能会放大K+稳态的破坏在存在的非致死性凋亡损伤，导致激活的凋亡级联反应和大量的神经元损伤。
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 μM 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 μM ouabain plus non-lethal C2-ceramide (5 μM) or β-amyloid 1–42 (5 μM), 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.