Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels.
Ca2+ permeability and Na+ conductance in cellular toxicity caused by hyperactive DEG/ENaC channels.
复制标题
由过度活跃的 DEG/ENaC 通道引起的细胞毒性中的 Ca2 渗透性和 Na 电导。
DOI：
10.1152/ajpcell.00247.2016
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Bianchi,Laura
中科院分区：
文献类型：
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作者：
Matthewman,Cristina;Miller-Fleming,TyneW;MillerRd,DavidM;Bianchi,Laura
过度激活的 DEG/ENaC 通道会导致细胞内 Ca2+ 过载介导的神经元死亡。秀丽隐杆线虫中的哺乳动物 ASIC1a 通道和 MEC-4(d) 神经毒性通道均传导 Na+ 和 Ca2+，这增加了直接 Ca2+ 通过这些通道流入导致细胞内 Ca2+ 过载的可能性。然而，我们证明了同源的C. elegansDEG/ENaC 通道 UNC-8(d) 不可渗透 Ca2+，但具有神经毒性，表明 Na+ 流入足以诱导细胞死亡。有趣的是，UNC-8(d) 由于爪蟾细胞表达系统中的细胞外 Ca2+ 阻断而显示出小电流。因此，MEC-4(d) 和 UNC-8(d) 在电流幅度和 Ca2+ 渗透性方面都不同。鉴于这两个通道在毒性方面表现出显着差异，我们想知道 Na+ 电导率与 Ca2+ 渗透率如何导致细胞死亡。为了解决这个问题，我们构建了一个 UNC-8/MEC-4 嵌合通道，该通道保留了 MEC-4 的钙渗透性，并表征了其在爪蟾细胞中的特性。我们的数据支持这样的假设：对于 Ca2+ 渗透性 DEG/ENaC 通道，Ca2+ 渗透性和 Na+ 电导都会导致毒性。然而，对于Ca2+不可渗透的DEG/ENaCs（例如UNC-8），我们的证据表明本构Na+电导足以诱导毒性，并且这种效应随着电流幅度的增加而增强。我们的工作进一步完善了不同通道特性对高度活跃的 DEG/ENaC 通道诱导的细胞毒性的贡献。
Hyperactivated DEG/ENaC channels cause neuronal death mediated by intracellular Ca2+overload. Mammalian ASIC1a channels and MEC-4(d) neurotoxic channels inCaenorhabditis elegansboth conduct Na+and Ca2+, raising the possibility that direct Ca2+influx through these channels contributes to intracellular Ca2+overload. However, we showed that the homologousC. elegansDEG/ENaC channel UNC-8(d) is not Ca2+permeable, yet it is neurotoxic, suggesting that Na+influx is sufficient to induce cell death. Interestingly, UNC-8(d) shows small currents due to extracellular Ca2+block in theXenopusoocyte expression system. Thus, MEC-4(d) and UNC-8(d) differ both in current amplitude and Ca2+permeability. Given that these two channels show a striking difference in toxicity, we wondered how Na+conductance vs. Ca2+permeability contributes to cell death. To address this question, we built an UNC-8/MEC-4 chimeric channel that retains the calcium permeability of MEC-4 and characterized its properties inXenopusoocytes. Our data support the hypothesis that for Ca2+-permeable DEG/ENaC channels, both Ca2+permeability and Na+conductance contribute to toxicity. However, for Ca2+-impermeable DEG/ENaCs (e.g., UNC-8), our evidence shows that constitutive Na+conductance is sufficient to induce toxicity, and that this effect is enhanced as current amplitude increases. Our work further refines the contribution of different channel properties to cellular toxicity induced by hyperactive DEG/ENaC channels.