Self-limited hyperexcitability:: Functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel
Self-limited hyperexcitability:: Functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel
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DOI：
10.1523/jneurosci.4453-07.2008
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发表时间：
2008-07-16
影响因子：
5.3
通讯作者：
Mantegazza, Massimo
中科院分区：
文献类型：
--
作者：
Cestele, Sandrine;Scalmani, Paolo;Mantegazza, Massimo
家族性偏瘫型偏头痛是一种常染色体显性遗传的先兆型偏头痛。导致FHM（3型）的突变已在编码神经元电压门控Na（v）1.1 Na（+）通道α亚基的基因SCN 1A中被鉴定出来，但功能研究已使用心脏Na（v）1.5亚型进行，观察到的效果与一些致癫痫突变相似。我们通过用人Na（v）1.1诱导tsA-201细胞和培养的神经元来研究FHM突变Q1489 K。我们发现，突变的通道，可以是一致的超兴奋性和hypoexcitability的门控特性的影响。模拟神经元放电和长去极化脉冲模仿promigraine条件显示，突变的效果是一个增益的功能与增加神经元放电一致。然而，在高频放电和长时间去极化过程中，这种效应会丧失功能。记录的转染神经元的放电表现出较高的放电频率在长放电的开始。这种诱导神经元过度兴奋的自限能力可能是偏头痛突变的一个特定特征，能够触发导致偏头痛的级联事件，并抵消癫痫发作典型的极端过度兴奋的发展。因此，我们发现FHM和家族性癫痫Nav1.1突变的功能效应可能存在差异。
Familial hemiplegic migraine (FHM) is an autosomal dominant inherited subtype of severe migraine with aura. Mutations causing FHM (type 3) have been identified in SCN1A, the gene encoding neuronal voltage-gated Na(v)1.1 Na(+) channel alpha subunit, but functional studies have been done using the cardiac Na(v)1.5 isoform, and the observed effects were similar to those of some epileptogenic mutations. We studied the FHM mutation Q1489K by transfecting tsA-201 cells and cultured neurons with human Na(v)1.1. We show that the mutation has effects on the gating properties of the channel that can be consistent with both hyperexcitability and hypoexcitability. Simulation of neuronal firing and long depolarizing pulses mimicking promigraine conditions revealed that the effect of the mutation is a gain of function consistent with increased neuronal firing. However, during high-frequency discharges and long depolarizations, the effect became a loss of function. Recordings of firing of transfected neurons showed higher firing frequency at the beginning of long discharges. This self-limited capacity to induce neuronal hyperexcitability may be a specific characteristic of migraine mutations, able to both trigger the cascade of events that leads to migraine and counteract the development of extreme hyperexcitability typical of epileptic seizures. Thus, we found a possible difference in the functional effects of FHM and familial epilepsy mutations of Nav1.1.