Sustained Ca2+-induced Ca2+-release underlies the post-glutamate lethal Ca2+ plateau in older cultured hippocampal neurons
Sustained Ca2+-induced Ca2+-release underlies the post-glutamate lethal Ca2+ plateau in older cultured hippocampal neurons
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DOI：
10.1016/s0014-2999(02)01843-5
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发表时间：
2002-07-05
影响因子：
5
通讯作者：
Thibault, O
中科院分区：
文献类型：
--
作者：
Clodfelter, GV;Porter, NM;Thibault, O
多项研究表明，在培养的神经元中，谷氨酸介导的兴奋性毒性损伤后，Ca2+长期升高，并且可能与即将发生的细胞死亡有关。最近，我们发现，随着培养中神经元年龄的增长，Ca2+的长期升高与年龄相关的兴奋性毒性脆弱性的增加特别相关。然而，在谷氨酸暴露期间和之后导致 Ca2+ 升高的 Ca2+ 的多种来源尚不清楚。在这里，我们检查了培养的海马神经元中与年龄相关的长期 Ca2+ 升高的 Ca2+ 来源。对咖啡因的研究表明，在年老和年轻的神经元中，细胞内储存的依赖于兰尼碱受体的可释放 Ca2+ 池是相似的。毒胡萝卜素可抑制细胞内钙储存再充盈，它不会模仿与年龄相关的长期 Ca2+ 升高，事实上，它可以部分降低它。 Ryanodine 可阻断 Ca2+ 诱导的 Ca2+ 释放 (CICR)，完全阻断谷氨酸暴露后与年龄相关的长期 Ca2+ 升高，但不会改变谷氨酸暴露期间的最大 Ca2+ 升高。因此，我们得出结论，持续的 CICR 在产生致命的、与年龄相关的、长期的 Ca2+ 升高中起着选择性和关键的作用，并且是与年龄相关的、神经元兴奋性毒性增强的脆弱性的可能机制。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Several studies have shown that a prolonged Ca2+ elevation follows a glutamate-mediated excitotoxic insult in cultured neurons, and may be associated with impending cell death. Recently, we showed that the prolonged Ca2+ elevation that emerges as neurons age in culture is specifically linked to an age-related increase in excitotoxic vulnerability. However, the multiple sources of Ca2+ that contribute to Ca2+ elevation during and after glutamate exposure are not well understood. Here, we examined the Ca2+ sources of the age-related prolonged Ca2+ elevation in cultured hippocampal neurons. Studies with caffeine showed that the ryanodine receptor-dependent releasable pool of Ca2+ from intracellular stores was similar in older and younger neurons. Thapsigargin, which inhibits intracellular store refilling, did not mimic the age-related prolonged Ca2+ elevation and, in fact, partially reduced it. Ryanodine, which blocks Ca2+-induced Ca2+ -release (CICR) from stores, completely blocked the age-related prolonged Ca2+ elevation following glutamate exposure but did not alter maximal Ca2+ elevation during the glutamate exposure. Thus, we conclude that sustained CICR plays a selective and key role in generating the lethal, age-related, prolonged Ca2+ elevation, and is the likely mechanism underlying age-related, enhanced vulnerability to excitotoxicity in neurons. (C) 2002 Elsevier Science B.V. All rights reserved.