Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: a periodic paralysis mutation in Na(V)1.4 (L689I).
Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: a periodic paralysis mutation in Na(V)1.4 (L689I).
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DOI：
10.1085/jgp.201210910
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Goldstein SA
中科院分区：
文献类型：
--
作者：
Silva JR;Goldstein SA
在骨骼肌中，NaV1.4电压门控钠通道的缓慢失活(SI)可防止自发去极化和疲劳。NAV1.4中损害SI的遗传突变破坏了活性诱导的通道可用性调节，并使患者容易患上高钾性周期性瘫痪。在本期的配套论文(席尔瓦和戈尔茨坦)中。2013年。J.Gen.Physiol.Http://dx.doi.org/10.1085/jgp.201210909)，：NAV1.4中的四个电压传感器负责在微秒内激活通道，随着SI的发展，1-160名S慢慢不能活动，并在SI恢复后恢复活动。通过连接的荧光探针评估的单个传感器运动在电压依赖性、时间进程和大小上是不相同的：DI和DII跟踪SI的开始，而DIII似乎反映SI的恢复。河豚毒素(TTX)抑制SI的发生以及DI和DII感受器的固定，从而推断出两者之间的因果联系。在这里，通过对NaV1.4通道与高钾性周期性麻痹突变的研究，证实了缓慢传感器固定和SI的关联；L689I在SI中产生复杂的变化，这些变化被发现直接体现在改变的传感器运动中。L689I去除了具有中间时间常数的SI成分(∼10 S)；该突变还阻碍了DI和DiI传感器在同一时间域上的固定化，以支持直接机械链接。一个概括SI的模型将中等SI的责任归因于DI和DII(10 S)，将慢分量归因于DIII(100 S)，后者解释了残余SI，不受L689I或TTX的阻碍。
In skeletal muscle, slow inactivation (SI) of NaV1.4 voltage-gated sodium channels prevents spontaneous depolarization and fatigue. Inherited mutations in NaV1.4 that impair SI disrupt activity-induced regulation of channel availability and predispose patients to hyperkalemic periodic paralysis. In our companion paper in this issue (Silva and Goldstein. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210909), the four voltage sensors in NaV1.4 responsible for activation of channels over microseconds are shown to slowly immobilize over 1–160 s as SI develops and to regain mobility on recovery from SI. Individual sensor movements assessed via attached fluorescent probes are nonidentical in their voltage dependence, time course, and magnitude: DI and DII track SI onset, and DIII appears to reflect SI recovery. A causal link was inferred by tetrodotoxin (TTX) suppression of both SI onset and immobilization of DI and DII sensors. Here, the association of slow sensor immobilization and SI is verified by study of NaV1.4 channels with a hyperkalemic periodic paralysis mutation; L689I produces complex changes in SI, and these are found to manifest directly in altered sensor movements. L689I removes a component of SI with an intermediate time constant (∼10 s); the mutation also impedes immobilization of the DI and DII sensors over the same time domain in support of direct mechanistic linkage. A model that recapitulates SI attributes responsibility for intermediate SI to DI and DII (10 s) and a slow component to DIII (100 s), which accounts for residual SI, not impeded by L689I or TTX.
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