A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons
A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons
复制标题
DOI：
10.1016/j.expneurol.2010.04.012
复制
发表时间：
2010-08-01
影响因子：
5.3
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Estacion, Mark;Gasser, Andreas;Waxman, Stephen G.
电压门控钠通道病变是许多兴奋性障碍的基础。编码成孔α亚基Na(v)1.1、Na(v)1.2和Na(v)1.7的基因SCN1A、SCN2A和SCN9A聚集在人类2号染色体上，这些基因的突变已被证明是癫痫、偏头痛和躯体性疼痛疾病的基础。编码Na(v)1.3的基因SCN3A是该基因簇的一部分，但直到最近才与任何突变联系起来。电荷中和突变。Na(v)1.3 D1/S5-6连接体中的K345Q最近在一名隐源性部分癫痫患者中被发现。Na(v)1.3/K354Q突变的致病性已从该残基在所有钠通道中的保守性和其在对照等位基因中的缺失推断出来，但功能分析仅限于心肌钠通道Na(v)1.5中相应的取代。由于相同的突变可能在不同的钠通道同种异构体中产生不同的影响，我们评估了K354Q在其天然Na(v)1.3通道中的突变，并研究了突变Na(v)1.3/K354Q通道对海马神经元兴奋性的影响。我们在这里发现，K354Q突变增强了Na(v)1.3的持续和斜坡电流，降低了电流阈值，并在海马神经元中产生自发放电和阵发性去极化移位样复合体。我们的数据为Na(v)1.3通道和海马神经元中第一个癫痫相关突变的致病性提供了病理生理学基础。(C) 2010爱思唯尔公司版权所有。
Voltage-gated sodium channelopathies underlie many excitability disorders. Genes SCN1A, SCN2A and SCN9A, which encode pore-forming alpha-subunits Na(v)1.1, Na(v)1.2 and Na(v)1.7, are clustered on human chromosome 2, and mutations in these genes have been shown to underlie epilepsy, migraine, and somatic pain disorders. SCN3A, the gene which encodes Na(v)1.3, is part of this cluster, but until recently was not associated with any mutation. A charge-neutralizing mutation. K345Q in the Na(v)1.3 D1/S5-6 linker has recently been identified in a patient with cryptogenic partial epilepsy. Pathogenicity of the Na(v)1.3/K354Q mutation has been inferred from the conservation of this residue in all sodium channels and its absence from control alleles, but functional analysis has been limited to the corresponding substitution in the cardiac muscle sodium channel Na(v)1.5. Since identical mutations may produce different effects within different sodium channel isoforms, we assessed the K354Q mutation within its native Na(v)1.3 channel and studied the effect of the mutant Na(v)1.3/K354Q channels on hippocampal neuron excitability. We show here that the K354Q mutation enhances the persistent and ramp currents of Na(v)1.3, reduces current threshold and produces spontaneous firing and paroxysmal depolarizing shift-like complexes in hippocampal neurons. Our data provide a pathophysiological basis for the pathogenicity of the first epilepsy-linked mutation within Na(v)1.3 channels and hippocampal neurons. (C) 2010 Elsevier Inc. All rights reserved.