Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms.
Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms.
复制标题
癫痫相关的松弛通道突变体通过两种不同的机制导致通道过度活跃。
DOI：
10.1016/j.celrep.2015.12.019
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发表时间：
2016-01-05
期刊：
影响因子：
8.8
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Tang QY;Zhang FF;Xu J;Wang R;Chen J;Logothetis DE;Zhang Z
从严重早发性癫痫患者中鉴定出12种钠激活钾通道（KCNT1，Slack）基因突变体。这些突变体的生物物理特性的变化和引起疾病的潜在机制仍然难以捉摸。在这里，我们报告说，12个突变中有7个增加，而一个突变降低了通道的钠敏感性。其中两个突变体仅在胞内Na+（[Na+]i）浓度约为80 mM时才表现出通道过活性。相反，单通道数据显示，所有12个突变体均增加了最大开放概率（Po）。我们的结论是，这些突变通道导致通道过度活动，主要是通过增加钠结合激活通道的能力，这是由其最大Po。这些致癫痫突变体的钠敏感性可能决定了这些突变体发挥其病理作用的[Na+]i浓度。
Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here we report that seven of the twelve mutations increase, while one mutation decreases the channel’s sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na+ ([Na+]i) concentration is approximately 80 mM. In contrast, single channel data reveal that all twelve mutants increase the maximal open probability (Po). We conclude that these mutant channels lead to channel over-activity predominantly by increasing the ability of sodium binding to activate the channel, which is indicated by its maximal Po. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na+]i concentration at which these mutants exert their pathological effects.