Nervous system KV7 disorders:: breakdown of a subthreshold brake
Nervous system KV7 disorders:: breakdown of a subthreshold brake
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DOI：
10.1113/jphysiol.2008.150656
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发表时间：
2008-04-01
影响因子：
5.5
通讯作者：
Lerche, Holger
中科院分区：
文献类型：
--
作者：
Maljevic, Snezana;Wuttke, Thomas V.;Lerche, Holger
在过去的10-15年中，通过发现三种常染色体显性遗传疾病的致病基因，已经确定了K（V）7（KCNQ）家族的电压门控K（+）通道：伴或不伴先天性耳聋的心律失常（长QT综合征）（KCNQ 1）、新生儿癫痫（KCNQ 2和KCNQ 3）和单纯进行性耳聋（KCNQ 4）。该基因家族的第五个成员（KCNQ 5）迄今为止没有受到疾病的影响。四个基因（KCNQ 2 -5）在神经系统中表达。本文综述了神经元K（V）7通道病，特别是KCNQ 2突变引起的良性家族性新生儿癫痫（BFNS）和周围神经过度兴奋（PNH、神经性肌强直、肌震颤）的最新研究结果。与KCNQ 2突变相关的表型谱可能比最初认为的更广泛，因为已经描述了患有严重癫痫和发育迟缓或Rolando癫痫的患者。关于潜在的分子病理生理学，已经表明，具有仅限于阈下电压的非常细微变化的突变可以引起BFNS，从而在人类疾病模型中证明这是这些通道调节神经元放电的相关电压范围。与PNH相关的两种突变诱导更严重的通道功能障碍，对野生型（WT）通道具有显性负效应。最后，K（V）7通道为神经元过度兴奋引起的疾病（如癫痫、神经性疼痛和偏头痛）的新治疗方法提供了有趣的靶点。瑞替加滨激活K（V）7的分子机制，目前正处于III期临床试验阶段，用于治疗药物耐药性局灶性癫痫，最近已被阐明为通过与孔区域结合来稳定开放构象。
Voltage-gatedK(+) channels of the K(V)7 (KCNQ) family have been identified in the last 10-15 years by discovering the causative genes for three autosomal dominant diseases: cardiac arrhythmia (long QT syndrome) with or without congenital deafness (KCNQ1), a neonatal epilepsy (KCNQ2 and KCNQ3) and progressive deafness alone (KCNQ4). A fifth member of this gene family (KCNQ5) is not affected in a disease so far. Four genes (KCNQ2-5) are expressed in the nervous system. This review is focused on recent findings on the neuronal K(V)7 channelopathies, in particular on benign familial neonatal seizures (BFNS) and peripheral nerve hyperexcitability (PNH, neuromyotonia, myokymia) caused by KCNQ2 mutations. The phenotypic spectrum associated with KCNQ2 mutations is probably broader than initially thought, as patients with severe epilepsies and developmental delay, or with Rolando epilepsy have been described. With regard to the underlying molecular pathophysiology, it has been shown that mutations with very subtle changes restricted to subthreshold voltages can cause BFNS thereby proving in a human disease model that this is the relevant voltage range for these channels to modulate neuronal firing. The two mutations associated with PNH induce much more severe channel dysfunction with a dominant negative effect on wild type (WT) channels. Finally, K(V)7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of K(V)7 activation by retigabine, which is in phase III clinical testing to treat pharmacoresistant focal epilepsies, has been recently elucidated as a stabilization of the open conformation by binding to the pore region.