Cell Rep：科学家发现遗传性癫痫病新成因

  近日，徐州医学院唐琼瑶、张赭教授课题组发表了成果发表于《细胞报告》，该研究成果发现了遗传性癫痫病新成因，阐释了Slack钾离子通道突变体导致癫痫的生物物理机制。

  遗传性癫痫是危害巨大的神经系统疾病，特别在婴幼儿中的癫痫病患中更加多发。近年来全基因组测序发现多种Slack 钾离子通道的突变体可以引起遗传性癫痫，但其生物物理机制及对疾病的预防和治疗的影响尚未阐明。

  日前，徐州医学院唐琼瑶、张赭教授课题组利用爪蟾卵母细胞表达系统，将12个Slack通道的突变体异位表达到爪蟾的卵母细胞中，并采用膜片钳技术测量了这些通道突变体的钠离子敏感性和单通道开放可能性的变化。研究表明这些突变体钠离子敏感性有变化，但是不是导致通道过度开放的主要原因。而通道开放最大可能性的提高才是通道突变体导致神经元异常放电的根本原因。

  这项研究不仅解释了Slack通道突变体导致Slack通道活性增加的生物物理因素，也为将来进一步在体研究将Slack通道作为癫痫治疗的药物靶点奠定了基础。这项研究也进一步指出只有在细胞内钠离子浓度超出正常生理浓度较大时，Slack通道突变体的开放可能性才有较大的变化。因此，在体神经元兴奋性在何种条件下受到Slack通道活性的调节尚需进一步的研究。

  原文链接：Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms

  原文摘要：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 12 mutations increase, wheras 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 ∼80 mM. In contrast, single-channel data reveal that all 12 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.