Intracellular Zn2+ increases contribute to the progression of excitotoxic Ca2+ increases in apical dendrites of CA1 pyramidal neurons.
Intracellular Zn2+ increases contribute to the progression of excitotoxic Ca2+ increases in apical dendrites of CA1 pyramidal neurons.
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DOI：
10.1016/j.neuroscience.2008.11.052
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发表时间：
2009-03-03
期刊：
影响因子：
3.3
通讯作者：
Shuttleworth CW
中科院分区：
文献类型：
--
作者：
Vander Jagt TA;Connor JA;Weiss JH;Shuttleworth CW
持续的细胞内Ca 2+升高是NMDA型谷氨酸受体过度激活后神经元损伤的公认贡献者。Zn 2+也可以参与兴奋性毒性变性，但这两种阳离子的相对贡献兴奋性毒性损伤的起始和进展尚不清楚。我们以前的结论是，延长NMDA暴露导致持续的Ca 2+增加，起源于CA 1神经元的顶端树突，然后缓慢地传播到整个神经元，并引起快速坏死损伤。然而，在这些研究中使用的荧光指示剂（Fura-6 F）也可能对Zn 2+作出反应，在目前的工作中，我们研究了Zn 2+对指示剂信号和沿着CA 1树突的退行性信号传导的进展的可能贡献。用N，N，N′，N′-四（2-吡啶基甲基）乙二胺（TPEN）选择性螯合Zn 2+可显著延迟，但不能阻止持续高水平Fura-6 F信号从树突到胞体的发展和进程。在Ca 2+超载反应，这对应于快速的神经元损伤，快速指标损失，也没有防止TPEN。在与Fura-6 F和Zn 2+选择性指示剂FluoZin-3共负载的单个CA 1神经元中评估胞质Zn 2+和Ca 2+水平之间的关系。NMDA暴露导致FluoZin-3增加的显著初始增加，这被TPEN阻止，但不是通过细胞外Zn 2+与Ca-EDTA螯合。与该结果一致，Ca-EDTA在NMDA期间不延迟Fura-6 F信号的进展。细胞外Ca 2+的去除减少，但不能阻止FluoZin-3的增加。这些结果表明，持续的Ca 2+增加确实是Fura-6 F信号在整个神经元中缓慢传播的基础，并且Ca 2+（而不是Zn 2+）增加最终是NMDA期间神经元损伤的原因。然而，从内源性来源的Zn 2+的动员导致显着的神经元Zn 2+增加，这反过来又有助于启动和进行性Ca 2+失调的进展机制。
Sustained intracellular Ca2+ elevation is a well-established contributor to neuronal injury following excessive activation of NMDA-type glutamate receptors. Zn2+ can also be involved in excitotoxic degeneration, but the relative contributions of these two cations to the initiation and progression of excitotoxic injury is not yet known. We previously concluded that extended NMDA exposure led to sustained Ca2+ increases that originated in apical dendrites of CA1 neurons and then propagated slowly throughout neurons and caused rapid necrotic injury. However the fluorescent indicator used in those studies (Fura-6F) may also respond to Zn2+, and in the present work we examine possible contributions of Zn2+ to indicator signals and to the progression of degenerative signaling along CA1 dendrites. Selective chelation of Zn2+ with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) significantly delayed, but did not prevent the development and progression of sustained high-level Fura-6F signals from dendrites to somata. Rapid indicator loss during the Ca2+ overload response, which corresponds to rapid neuronal injury, was also not prevented by TPEN. The relationship between cytosolic Zn2+ and Ca2+ levels was assessed in single CA1 neurons co-loaded with Fura-6F and the Zn2+-selective indicator FluoZin-3. NMDA exposure resulted in significant initial increases in FluoZin-3 increases that were prevented by TPEN, but not by extracellular Zn2+ chelation with Ca-EDTA. Consistent with this result, Ca-EDTA did not delay the progression of Fura-6F signals during NMDA. Removal of extracellular Ca2+ reduced, but did not prevent FluoZin-3 increases. These results suggest that sustained Ca2+ increases indeed underlie Fura-6F signals that slowly propagate throughout neurons, and that Ca2+ (rather than Zn2+) increases are ultimately responsible for neuronal injury during NMDA. However, mobilization of Zn2+ from endogenous sources leads to significant neuronal Zn2+ increases, that in turn contribute to mechanisms of initiation and progression of progressive Ca2+ deregulation.
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