Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy
Subthreshold changes of voltage-dependent activation of the KV7.2 channel in neonatal epilepsy
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DOI：
10.1016/j.nbd.2006.06.011
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发表时间：
2006-10
影响因子：
6.1
通讯作者：
Jessica L Hunter;S. Maljevic;A. Shankar;A. Siegel;Barbara Weissman;Philip J. Holt;L. Olson;H. Lerche;A. Escayg
中科院分区：
文献类型：
--
作者：
Jessica L Hunter;S. Maljevic;A. Shankar;A. Siegel;Barbara Weissman;Philip J. Holt;L. Olson;H. Lerche;A. Escayg
良性家族性新生儿惊厥(BFNC)是由编码K+通道KV7.2和KV7.3的基因KCNQ2和KCNQ3的显性突变引起的一种癫痫疾病。我们在两个BFNC家系中发现了两个新的KCNQ2突变。一个突变预测了一个缺失通道孔区的截短蛋白(S247X)，另一个突变导致KV7.2的S2段的氨基酸替换为S122L。与野生型(WT)KV7.2相比，S122L突变型通道在非洲爪哇卵母细胞中的功能分析显示，激活曲线的正移和斜率增加，导致动作电位的亚阈值范围内的电流显著减少(在−50 mV时减少75%)。我们的结果确立了KV7.2 S2片段在电压依赖性通道门控中的重要作用，并在人类疾病中证明了亚阈值电压可能代表了该K+通道调节神经元放电的生理相关范围。
Benign familial neonatal convulsions (BFNC) is an epileptic disorder caused by dominant mutations in the genes KCNQ2 and KCNQ3 encoding the K+channels KV7.2 and KV7.3. We identified two novel KCNQ2 mutations in two BFNC families. One mutation predicted a truncated protein (S247X) that lacks the channel's pore region, the other resulted in the amino acid substitution S122L in the S2 segment of KV7.2. In comparison to wild-type (WT) KV7.2, functional analysis of S122L mutant channels in Xenopus oocytes revealed a significant positive shift and increased slope of the activation curve leading to significant current reduction in the subthreshold range of an action potential (75% reduction at −50 mV). Our results establish an important role of the KV7.2 S2 segment in voltage-dependent channel gating and demonstrate in a human disease that subthreshold voltages are likely to represent the physiologically relevant range for this K+channel to regulate neuronal firing.