Toxic Role of K+ Channel Oxidation in Mammalian Brain
Toxic Role of K+ Channel Oxidation in Mammalian Brain
复制标题
DOI：
10.1523/jneurosci.6153-11.2012
复制
发表时间：
2012-03-21
影响因子：
5.3
通讯作者：
Sesti, Federico
中科院分区：
文献类型：
--
作者：
Cotella, Diego;Hernandez-Enriquez, Berenice;Sesti, Federico
钾 (K+) 通道对于神经元信号传导和生存至关重要。在这里，我们证明这些蛋白质是哺乳动物大脑中活性氧的靶标，它们的氧化会导致神经病变。因此，在皮层和海马中大量表达的 KCNB1 (Kv2.1) 通道在暴露于氧化剂时形成寡聚体。这些寡聚体在老年小鼠大脑中的含量比年轻小鼠高 10 倍。氧化剂诱导的野生型 KCNB1 寡聚化增强了遭受氧化损伤的神经元细胞的凋亡。因此，通过将保守的半胱氨酸突变为丙氨酸（C73A）而获得的抗氧化的 KCNB1 变体具有神经保护作用。 KCNB1 的氧化具有毒性，这一事实表明，这种机制可能会导致以高水平氧化应激为特征的神经病变，例如阿尔茨海默病 (AD)。因此，AD 三重转基因小鼠模型 (3xTg-AD) 的大脑中 KCNB1 通道的氧化加剧。 C73A 变体可保护神经元细胞免受与 β-淀粉样肽 (A beta(1-42)) 孵育诱导的细胞凋亡。在模拟 AD 各方面的无脊椎动物模型（秀丽隐杆线虫）中，C73A-KCNB1 同源物 (C113S-KVS-1) 保护特定神经元免遭人 A beta(1-42) 异位表达诱导的细胞凋亡。总之，这些数据强调了神经退行性疾病中一种新的毒性机制。
Potassium (K+) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were similar to 10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with beta-amyloid peptide (A beta(1-42)). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human A beta(1-42). Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease.