The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition
The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition
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DOI：
10.1177/1073858416645087
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发表时间：
2016-12-01
期刊：
影响因子：
5.6
通讯作者：
Poduri, Annapurna
中科院分区：
文献类型：
--
作者：
Kahle, Kristopher T.;Khanna, Arjun R.;Poduri, Annapurna
由SLC12A5编码的阳离子-氯-共转运体KCC2是生物体在进化过程中产生和维持GABA能快速突触抑制所必需的。这些发现表明KCC2缺乏可能在人类癫痫的发病机制中发挥作用，但直到最近才有两条遗传证据证实了这一点。第一个是发现SLC12A5杂合性错义多态，导致KCC2依赖的氯-排出能力下降，在一个遗传性热性癫痫的澳大利亚家系和一个患有严重遗传性全身性癫痫(GGE)的法国-加拿大队列中发现。第二个是在一种严重的早发性孟德尔病患者中发现了SLC12A5隐性功能丧失突变，这种疾病被称为婴儿期癫痫伴迁移性局灶性癫痫(EIMFS)。这些发现共同支持了这样的范式，即精确调控KCC2活性是人类突触抑制所必需的，并且由于基因剂量、内在活性或外部调节的影响，遗传编码的KCC2功能障碍可以影响患者的癫痫表型。因此，KCC2可能成为一种新的抗癫痫策略的靶点，旨在通过促进氯-排出来恢复对GABA的抑制。这类药物可能与耐药癫痫相关，也可能与其他以突触过度兴奋为特征的疾病有关，例如谱系自闭症障碍。
The cation-Cl- cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl- extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed epilepsy of infancy with migrating focal seizures (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl- extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders.