Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels.
Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels.
复制标题
突变的 LGI1 抑制癫痫发作诱导的 Kv4.2 钾通道运输。
DOI：
10.1111/j.1471-4159.2011.07605.x
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发表时间：
2012
影响因子：
4.7
通讯作者：
Anderson,MatthewP
中科院分区：
文献类型：
--
作者：
Smith,StephenEP;Xu,Lin;Kasten,MichaelR;Anderson,MatthewP
神经化学杂志。（2012）120，611- 621.离子通道的活性依赖性再分布介导神经元回路可塑性和稳态，并且可以提供对癫痫发作的促癫痫或补偿性抗癫痫反应。丘脑皮层神经元将感觉信息传递到大脑皮层，并通过相互的皮质丘脑连接在癫痫发作期间被强烈激活。因此，我们评估是否癫痫发作改变离子通道表面表达和随之而来的丘脑皮质神经元的神经生理功能。我们报告了癫痫发作触发兴奋性突触后电流（EPSC）样电流诱导的相位放电快速（<2 h）降低，与瞬时A型K+电流增加相关。 癫痫发作还迅速将A型K+通道亚基Kv4.2重新分布到神经元表面，这暗示了K+电流增加的分子底物。在体外应用谷氨酸可模拟这种作用，表明谷氨酸能传递的直接作用。重要的是，富含亮氨酸的胶质瘤失活蛋白1（LGI 1），一种突变引起人类部分癫痫的分泌性突触蛋白，调节了这种癫痫发作诱导的电路反应。人类癫痫相关显性负性截短突变体LGI 1抑制癫痫发作诱导的相位放电抑制、A型K+电流增加和Kv4.2表面表达的募集（体内和体外）。结果确定了丘脑皮质神经元癫痫发作涉及Kv4.2表面招聘与阻尼相位发射的反应。结果还确定了受损的癫痫发作诱导的A型K+电流增加是由常染色体显性外侧颞叶癫痫基因突变体产生的额外缺陷，可能导致癫痫发作疾病。
J. Neurochem.(2012)120, 611–621.AbstractActivity‐dependent redistribution of ion channels mediates neuronal circuit plasticity and homeostasis, and could provide pro‐epileptic or compensatory anti‐epileptic responses to a seizure. Thalamocortical neurons transmit sensory information to the cerebral cortex and through reciprocal corticothalamic connections are intensely activated during a seizure. Therefore, we assessed whether a seizure alters ion channel surface expression and consequent neurophysiologic function of thalamocortical neurons. We report a seizure triggers a rapid (< 2 h) decrease of excitatory postsynaptic current (EPSC)‐like current‐induced phasic firing associated with increased transient A‐type K+current. Seizures also rapidly redistributed the A‐type K+channel subunit Kv4.2 to the neuronal surface implicating a molecular substrate for the increased K+current. Glutamate appliedin vitromimicked the effect, suggesting a direct effect of glutamatergic transmission. Importantly, leucine‐rich glioma‐inactivated‐1 (LGI1), a secreted synaptic protein mutated to cause human partial epilepsy, regulated this seizure‐induced circuit response. Human epilepsy‐associated dominant‐negative‐truncated mutant LGI1 inhibited the seizure‐induced suppression of phasic firing, increase of A‐type K+current, and recruitment of Kv4.2 surface expression (in vivoandin vitro). The results identify a response of thalamocortical neurons to seizures involving Kv4.2 surface recruitment associated with dampened phasic firing. The results also identify impaired seizure‐induced increases of A‐type K+current as an additional defect produced by the autosomal dominant lateral temporal lobe epilepsy gene mutant that might contribute to the seizure disorder.