Regulation of membrane excitability: a convergence on voltage-gated sodium conductance.
Regulation of membrane excitability: a convergence on voltage-gated sodium conductance.
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DOI：
10.1007/s12035-014-8674-0
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发表时间：
2015-02
影响因子：
5.1
通讯作者：
Baines, Richard A.
中科院分区：
文献类型：
--
作者：
Lin, Wei-Hsiang;Baines, Richard A.
电压门控钠通道（Nav）在调节神经元兴奋性中起关键作用。Nav表达和/或功能的异常调节可导致神经元活性的失衡，这可进展为癫痫。Nav活性的调节通过多种机制的协调来实现，包括RNA选择性剪接和翻译抑制。对这些调控机制的理解因广泛的遗传冗余而变得复杂：哺乳动物基因组编码10个Navs。相比之下，果蝇（Drosophila melanogaster）的基因组只包含一个由麻痹剂（DmNa v）编码的Nav同源物。DmNa v中剪接的分析显示变体表现出不同的门控特性，包括持续钠电流（INaP）的变化幅度。Pasilla（一种已鉴定的RNA剪接因子）的剪接改变了INaP的大小，这是活性依赖性机制的一部分。增强的INaP促进与果蝇中的类似果蝇行为相关的膜超兴奋性。Nova-2是一种哺乳动物Pasilla同源物，也与Navs的剪接有关，此外，小鼠基因敲除显示出类似于哺乳动物的行为。在果蝇和哺乳动物中，Navs的表达水平也通过翻译抑制机制进行调节。翻译抑制因子Pumilio（Pum）可与Na v转录本结合，抑制正常的翻译过程，从而调节神经元钠电流（INa）密度。Pum 2缺陷小鼠表现出自发性EEG异常。总之，Nav功能和/或表达的异常调节通常是致癫痫的。因此，更好地了解通过RNA选择性剪接和Navs的翻译抑制调节膜兴奋性应该为治疗癫痫提供新的线索。
The voltage-gated sodium channel (Nav) plays a key role in regulation of neuronal excitability. Aberrant regulation of Nav expression and/or function can result in an imbalance in neuronal activity which can progress to epilepsy. Regulation of Nav activity is achieved by coordination of a multitude of mechanisms including RNA alternative splicing and translational repression. Understanding of these regulatory mechanisms is complicated by extensive genetic redundancy: the mammalian genome encodes ten Navs. By contrast, the genome of the fruitfly, Drosophila melanogaster, contains just one Nav homologue, encoded by paralytic (DmNa v). Analysis of splicing in DmNa v shows variants exhibit distinct gating properties including varying magnitudes of persistent sodium current (INaP). Splicing by Pasilla, an identified RNA splicing factor, alters INaP magnitude as part of an activity-dependent mechanism. Enhanced INaP promotes membrane hyperexcitability that is associated with seizure-like behaviour in Drosophila. Nova-2, a mammalian Pasilla homologue, has also been linked to splicing of Navs and, moreover, mouse gene knockouts display seizure-like behaviour. Expression level of Navs is also regulated through a mechanism of translational repression in both flies and mammals. The translational repressor Pumilio (Pum) can bind to Na v transcripts and repress the normal process of translation, thus regulating sodium current (INa) density in neurons. Pum2-deficient mice exhibit spontaneous EEG abnormalities. Taken together, aberrant regulation of Nav function and/or expression is often epileptogenic. As such, a better understanding of regulation of membrane excitability through RNA alternative splicing and translational repression of Navs should provide new leads to treat epilepsy.
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影响因子：
4.7
作者：
CONSTANTI, A
通讯作者：
CONSTANTI, A
替代剪接调节1型电压门控钠通道的失活，通过在第一个S3-S4接头中切换氨基酸。
DOI：
10.1074/jbc.m111.250225
发表时间：
2011-10-21
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fletcher EV;Kullmann DM;Schorge S
通讯作者：
Schorge S
DOI：
10.1073/pnas.201284398
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chagnovich, D;Lehmann, R
通讯作者：
Lehmann, R
影响因子：
4.5
作者：
Chatelier, Aurelien;Zhao, Juan;Chahine, Mohamed
通讯作者：
Chahine, Mohamed
影响因子：
7.7
作者：
Eom T;Zhang C;Wang H;Lay K;Fak J;Noebels JL;Darnell RB
通讯作者：
Darnell RB