Seizure suppression through manipulating splicing of a voltage-gated sodium channel.
Seizure suppression through manipulating splicing of a voltage-gated sodium channel.
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DOI：
10.1093/brain/awv012
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Baines RA
中科院分区：
文献类型：
--
作者：
Lin WH;He M;Baines RA
电压门控持续钠电流（INaP）是抗癫痫药物的一个易处理的靶点。使用一种专注于INaP减少的策略，Lin等人鉴定了95种电压门控钠通道剪接的调节剂，RNAi敲低这些调节剂可减少果蝇的癫痫发作持续时间。操纵剪接调节子可以改善癫痫的控制。癫痫发作可由电压门控持续钠电流表达增加引起。虽然许多临床批准的抗癫痫药物靶向电压门控持续钠电流，但没有一种药物专门抑制该电流而不对瞬时电压门控钠电流产生不利影响。实现更具选择性的阻滞对于癫痫的治疗具有显著的潜力。最近的研究表明，电压门控持续钠电流的幅度是由选择性剪接提供了一个新的途径控制癫痫发作的可能性。在这项研究中，我们确定了291剪接调节，敲低，改变果蝇电压门控钠通道的剪接，有利于包括外显子K，而不是相互排斥的外显子L。这种变化与电压门控持续性钠电流的显著降低（不改变瞬时电压门控钠电流）和该模型昆虫中癫痫发作的挽救相关。RNA干扰介导的敲低，在两个不同的癫痫发作突变体中，显示95这些调节剂足以显着减少癫痫发作持续时间。此外，大多数抑制癫痫发作活动的突变体，这表明他们是保守的途径的一部分，因此，可能是最佳的候选人，以推进哺乳动物的研究。我们通过显示使用小分子抑制剂抑制一系列调节剂对减少癫痫发作同样有效，为此类研究提供了原理证明。果蝇钠通道的剪接与哺乳动物钠通道有许多相似之处，包括改变电压门控持续钠电流的幅度。我们的研究提供了动力，调查是否操纵哺乳动物电压门控钠通道的剪接可能是可利用的，以提供有效的癫痫控制。
Voltage-gated persistent sodium current (INaP) is a tractable target for antiepileptic drugs. Using a strategy focused on INaP reduction, Lin et al. identify 95 regulators of voltage-gated sodium channel splicing for which RNAi knockdown reduces seizure duration in Drosophila. Manipulation of splicing regulators could improve control of epilepsy. Seizure can result from increased voltage-gated persistent sodium current expression. Although many clinically-approved antiepileptic drugs target voltage-gated persistent sodium current, none exclusively repress this current without also adversely affecting the transient voltage-gated sodium current. Achieving a more selective block has significant potential for the treatment of epilepsy. Recent studies show that voltage-gated persistent sodium current amplitude is regulated by alternative splicing offering the possibility of a novel route for seizure control. In this study we identify 291 splicing regulators that, on knockdown, alter splicing of the Drosophila voltage-gated sodium channel to favour inclusion of exon K, rather than the mutually exclusive exon L. This change is associated with both a significant reduction in voltage-gated persistent sodium current, without change to transient voltage-gated sodium current, and to rescue of seizure in this model insect. RNA interference mediated knock-down, in two different seizure mutants, shows that 95 of these regulators are sufficient to significantly reduce seizure duration. Moreover, most suppress seizure activity in both mutants, indicative that they are part of well conserved pathways and likely, therefore, to be optimal candidates to take forward to mammalian studies. We provide proof-of-principle for such studies by showing that inhibition of a selection of regulators, using small molecule inhibitors, is similarly effective to reduce seizure. Splicing of the Drosophila sodium channel shows many similarities to its mammalian counterparts, including altering the amplitude of voltage-gated persistent sodium current. Our study provides the impetus to investigate whether manipulation of splicing of mammalian voltage-gated sodium channels may be exploitable to provide effective seizure control.
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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
影响因子：
5.6
作者：
Anderson LL;Thompson CH;Hawkins NA;Nath RD;Petersohn AA;Rajamani S;Bush WS;Frankel WN;Vanoye CG;Kearney JA;George AL Jr
通讯作者：
George AL Jr
影响因子：
6.1
作者：
Koeller, Hajira B.;Ross, M. Elizabeth;Glickstein, Sara B.
通讯作者：
Glickstein, Sara B.
DOI：
10.1016/s0306-3623(97)00023-2
发表时间：
1997-11-01
期刊：
GENERAL PHARMACOLOGY-THE VASCULAR SYSTEM
影响因子：
--
作者：
Kohno, K;Niwa, M;Fujimura, H
通讯作者：
Fujimura, H
影响因子：
6.1
作者：
Grabenstatter HL;Del Angel YC;Carlsen J;Wempe MF;White AM;Cogswell M;Russek SJ;Brooks-Kayal AR
通讯作者：
Brooks-Kayal AR