Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein
Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein
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DOI：
10.1074/jbc.m206769200
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发表时间：
2003-01-24
影响因子：
4.8
通讯作者：
Van Leuven, F
中科院分区：
文献类型：
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作者：
Herms, J;Schneider, I;Van Leuven, F
突变的早老素-1 (PSI) 会增加淀粉样肽的产生，减弱钙的钙进入 (CCE)，并增加内质网 (ER) 的钙释放。在这里，我们测量了六种不同的转基因和基因消除小鼠组合的海马神经元的细胞内游离 Ca2+ 浓度，以证明突变 PSI 直接减弱 CCE，而不依赖于淀粉样前体蛋白 (APP) 的表达。另一方面，毒胡萝卜素诱导突变型 PS1 神经元内质网释放的 Ca2+ 增加，显然取决于 APP 的存在及其 PS1 的加工，即淀粉样肽和 APP C99 片段的生成。这一观察结果得到了毒胡萝卜素诱导的 PS1 缺陷神经元胞质 [Ca2+](i) 增加的证实，这些神经元由于 γ 分泌酶活性缺陷而积累了 C99 片段。此外，突变体APP[V717I]在PS1缺陷神经元中的共表达进一步增加了内质网钙储存的表观大小，同时APP加工产物水平也增加了。我们得出结论，突变 PSI 通过两种不同的作用来解除神经元钙稳态的调节：（i）独立于 APP 直接减弱细胞表面的 CCE； (ii) 通过 APP 的加工和淀粉样肽和 C99 片段的生成间接增加 ER 钙储备。
Mutant presenilin-1 (PSI) increases amyloid peptide production, attenuates capacitative calcium entry (CCE), and augments calcium release from the endoplasmatic reticulum (ER). Here we measured the intracellular free Ca2+ concentration in hippocampal neurons from six different combinations of transgenic and gene-ablated mice to demonstrate that mutant PSI attenuated CCE directly, independent of the expression of the amyloid precursor protein (APP). On the other hand, increased Ca2+ release from the ER in mutant PS1 neurons, as induced by thapsigargin, was clearly dependent on the presence of APP and its processing by PS1, i.e. on the generation of the amyloid peptides and the APP C99 fragments. This observation was corroborated by the thapsigargin-induced increase in cytosolic [Ca2+](i) in PS1 deficient neurons, which accumulate C99 fragments due to deficient gamma-secretase activity. Moreover, co-expression of mutant APP[V717I] in PS1-deficient neurons further increased the apparent size of the ER calcium stores in parallel with increasing levels of the APP processing products. We conclude that mutant PSI deregulates neuronal calcium homeostasis by two different actions: (i) direct attenuation of CCE at the cell-surface independent of APP; and (ii) indirect increase of ER-calcium stores via processing of APP and generation of amyloid peptides and C99 fragments.