A preferential role for glycolysis in preventing the anoxic depolarization of rat hippocampal area CA1 pyramidal cells
A preferential role for glycolysis in preventing the anoxic depolarization of rat hippocampal area CA1 pyramidal cells
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DOI：
10.1523/jneurosci.4157-04.2005
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发表时间：
2005-01-26
影响因子：
5.3
通讯作者：
Attwell, D
中科院分区：
文献类型：
--
作者：
Allen, NJ;Káradóttir, R;Attwell, D
在脑缺氧或缺血时，三磷酸腺苷水平的降低会导致跨膜离子梯度突然下降[缺氧去极化(AD)]。这通过逆转谷氨酸转运体的操作来释放谷氨酸，从而触发神经元死亡。通过全细胞钳制CA1锥体细胞，我们研究了在去除O(2)和葡萄糖的情况下，海马片中延缓AD发生的能量储存。在P12切片糖酵解和线粒体ATP产生受阻的情况下，AD发生的时间类似于33℃下的7min，反映了代谢活动消耗现有的ATP和磷酸肌酸以及随后的离子梯度降低所需的时间。在没有葡萄糖的情况下，允许糖原驱动的糖酵解使AD延迟5.5分钟，而超融合葡萄糖阻止AD发生1小时。当糖酵解被阻止时，当线粒体发挥作用时，到AD的潜伏期延长了6.5分钟，这表明糖酵解下游的代谢产物(丙酮酸、柠檬酸循环中间体和氨基酸氧化)为氧化磷酸化提供了显著的能量储备。在糖酵解受阻但线粒体功能正常的情况下，灌流乳酸并没有显著延缓AD的发生，这表明乳酸产生的ATP远低于内源性代谢产物。这些数据显示了糖酵解在预防AD方面的优先作用。他们还定义了海马区能量存储池大小的等级，并表明在能量缺乏的情况下，脑内神经胶质乳酸产生的ATP可能并不显著。
During brain anoxia or ischemia, a decrease in the level of ATP leads to a sudden decrease in transmembrane ion gradients [ anoxic depolarization (AD)]. This releases glutamate by reversing the operation of glutamate transporters, which triggers neuronal death. By whole-cell clamping CA1 pyramidal cells, we investigated the energy stores that delay the occurrence of the AD in hippocampal slices when O(2) and glucose are removed. With glycolytic and mitochondrial ATP production blocked in P12 slices, the AD occurred in similar to 7 min at 33 degreesC, reflecting the time needed for metabolic activity to consume the existing ATP and phosphocreatine, and for subsequent ion gradient decrease. Allowing glycolysis fueled by glycogen, in the absence of glucose, delayed the AD by 5.5 min, whereas superfused glucose prevented the AD for > 1 h. With glycolysis blocked, the latency to the AD was 6.5 min longer when mitochondria were allowed to function, demonstrating that metabolites downstream of glycolysis ( pyruvate, citric acid cycle intermediates, and amino acid oxidation) provide a significant energy store for oxidative phosphorylation. With glycolysis blocked but mitochondria functioning, superfusing lactate did not significantly delay the AD, showing that ATP production from lactate is much less than that from endogenous metabolites. These data demonstrate a preferential role for glycolysis in preventing the AD. They also define a hierarchy of pool sizes for hippocampal energy stores and suggest that brain ATP production from glial lactate may not be significant in conditions of energy deprivation.