INTRACELLULAR CATIONS AND EXCITOTOXICITY

描述：(改编自申请人的摘要)：人们普遍认为 谷氨酸引发的急性神经元损伤依赖于钙离子内流 而最迅速的损伤形式是由激活的 N-甲基-D-天冬氨酸受体。然而，在之前的研究中，使用了 神经元损伤的体外模型一直很难解释 N-甲基-D-天冬氨酸受体激活神经毒性效应的特异性 区分有毒和无毒细胞内钙离子的难度 改变。在重新评估将钙变化与神经元联系起来的研究中 很明显，有必要重新考虑 与损伤相关的钙变化的大小，因为以前 研究可能没有提供准确的结果。此外，不受赏识 几种常用荧光染料对染料的选择性问题 细胞内的二价阳离子表明镁和锌也应该是 被认为是兴奋性毒性损伤的候选神经毒素。 这些研究的长期目标是通过以下方式了解离子机制 谷氨酸会杀死神经元。申请者计划：确定非NMDA 受体激动剂引起急性神经元损伤如果钙离子的大小 它们引起的变化是增加的；确定 谷氨酸刺激神经元细胞内镁的变化，以及谷氨酸如何 这改变了线粒体的功能；决定了细胞内的大小 锌的变化及其与神经元损伤的关系；以及，确定 保护神经元免受锌介导的损伤的机制。有一个号码 各种阳离子介导的潜在重要相互关系 伤害的形式，建议的方法是调查这些 关系，也是为了利用方法论上的相似性， 适用于测量每个感兴趣的离子。

DESCRIPTION: (Adapted from applicant's abstract): It is widely appreciated that glutamate-triggered acute neuronal injury is dependent on calcium entry into neurons and that the most rapid form of injury is mediated by the activation of N-methyl-D-aspartate receptors. However, in previous studies that have used in vitro models of neuronal injury it has been difficult to account for the specificity of the neurotoxic effects of NMDA receptor activation because of the difficulty in distinguishing toxic and non-toxic intracellular calcium changes. In re-evaluating the studies that link calcium changes to neuronal injury it becomes apparent that it is necessary to reconsider the issues of the magnitude of calcium changes that are associated with injury because previous studies may not have provided accurate results. In addition, unappreciated issues of the selectivity of the commonly used fluorescent dyes for intracellular divalent cations suggest that magnesium and zinc should also be considered as candidate neurotoxins in excitotoxic injury. The long-term goal of these studies is to understand the ionic mechanisms by which glutamate kills neurons. The applicants plan to: determine if non-NMDA receptor agonists induce acute neuronal injury if the magnitude of the calcium change they induce is increased; determine if the magnitude of the intracellular Mg change in neurons is stimulated by glutamate, and how would this alter mitochondrial function; determine the magnitude of intracellular zinc changes and how they may relate to neuronal injury; and, to determine the mechanisms neurons are protected from zinc-mediated injury. There are a number of potentially important interrelationships between the various cation-mediated forms of injury, and the proposed approach is to investigate these relationships, and, also to exploit the similarities in methodology that can be adapted to measure each ion of interest.