Roles of volume-sensitive chloride channel in excitotoxic neuronal injury
Roles of volume-sensitive chloride channel in excitotoxic neuronal injury
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DOI：
10.1523/jneurosci.4694-06.2007
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发表时间：
2007-02-07
影响因子：
5.3
通讯作者：
Okada, Yasunobu
中科院分区：
文献类型：
--
作者：
Inoue, Hana;Okada, Yasunobu
兴奋性毒性与中风、脑创伤和一些神经退行性疾病有关。在大脑中，在兴奋性毒性侮辱期间，神经元在胞体和树突中都经历了迅速的肿胀。沿着树突的局灶性肿胀称为静脉曲张，被认为是急性兴奋性毒性神经元损伤的标志。然而，目前还不清楚是什么途径参与了神经元阴离子通量，从而导致兴奋性毒性静脉曲张的形成和消退。在这里，我们评估了容量敏感的外向整流(VSOR)Cl-通道在小鼠皮质神经元兴奋性毒性反应中的作用。全细胞膜片钳记录显示，NMDA可激活培养神经元的VSORCl-通道。此外，该通道在精索静脉曲张中的强健表达被细胞内和制霉菌素穿孔的囊泡贴片技术所证实。VSOR通道阻滞剂，而不是GABA(A)受体和Cl-转运体阻断剂，不仅可以阻止亚致死性兴奋毒性刺激后静脉曲张的消退，而且可以阻止因长期暴露NMDA而导致的皮质神经元持续静脉曲张形成后的坏死性死亡。本实验首次证实了VSOR Cl-通道在锥体感觉神经元中的表达。NMDA诱导的脑片坏死性神经元死亡在很大程度上可被VSOR Cl-通道阻断剂抑制，但不能被GABA(A)受体阻断剂抑制。这些结果表明，VSOR Cl-通道对神经元的兴奋性毒性具有双重的交互作用，既是兴奋毒性刺激剂清除后静脉曲张恢复的主要阴离子通路，也是在长时间兴奋毒性损伤下导致皮质神经元坏死的持续性静脉曲张形成的主要阴离子通路。
Excitotoxicity is associated with stroke, brain trauma, and a number of neurodegenerative disorders. In the brain, during excitotoxic insults, neurons undergo rapid swelling in both the soma and dendrites. Focal swellings along the dendrites called varicosities are considered to be a hallmark of acute excitotoxic neuronal injury. However, it is not clear what pathway is involved in the neuronal anion flux that leads to the formation and resolution of excitotoxic varicosities. Here, we assessed the roles of the volume-sensitive outwardly rectifying (VSOR) Cl- channel in excitotoxic responses in mouse cortical neurons. Whole-cell patch-clamp recordings revealed that the VSOR Cl- channel in cultured neurons was activated by NMDA exposure. Moreover, robust expression of this channel on varicosities was confirmed by on-cell and nystatin-perforated vesicle patch techniques. VSOR channel blockers, but not blockers of GABA(A) receptors and Cl- transporters, abolished not only varicosity resolution after sublethal excitotoxic stimulation but also necrotic death after sustained varicosity formation induced by prolonged NMDA exposure in cortical neurons. The present slice-patch experiments demonstrated, for the first time, expression of the VSOR Cl- channels in somatosensory pyramidal neurons. NMDA-induced necrotic neuronal death in slice preparations was largely suppressed by a blocker of the VSOR Cl- channel but not of the GABA(A) receptor. These results indicate that VSOR Cl- channels exert dual, reciprocal actions on neuronal excitotoxicity by serving as major anionic pathways both for varicosity recovery after washout of an excitotoxic stimulant and for persistent varicosity formation under prolonged excitotoxic insults leading to necrosis in cortical neurons.