PDF(Pubmed)
Abstract：
The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na+-dependent K+ (KNa) and voltage-dependent sodium (NaV) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of NaV channel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment and of axonal NaV immunostaining is increased in both neuron types. Our study on the coordinate regulation of KNa currents and the expression of NaV channels may provide an avenue for understanding and treating epilepsies and other neurological disorders.
摘要：
KCNT1基因编码钠激活钾通道Slack（KCNT1，KNa1.1），神经元兴奋性的调节器。人类的功能增益突变导致皮层网络过度兴奋，癫痫发作,和严重的智力残疾。使用表达Slack-R455H突变的小鼠模型，我们发现，在兴奋性和抑制性皮质神经元中，Na依赖性K（KNa）和电压依赖性钠（NaV）电流均增加。这些增加的电流，然而,增强兴奋性神经元的放电，但抑制抑制性神经元的放电。我们进一步表明，NaV通道亚基的表达，特别是NaV1.6的水平上调，并且两种神经元类型的轴突初始节段和轴突NaV免疫染色的长度都增加。我们对KNa电流和NaV通道表达的协调调节的研究可能为理解和治疗癫痫和其他神经系统疾病提供了途径。
