Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia
Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia
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DOI：
10.1212/01.wnl.0000265397.70057.d8
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发表时间：
2008-03-04
期刊：
影响因子：
9.9
通讯作者：
Cannon, Stephen C.
中科院分区：
文献类型：
--
作者：
Webb, Jadon;Cannon, Stephen C.
背景资料：骨骼肌电压门控钠通道（NaV1.4）的错义突变是几种临床上不同形式的周期性麻痹和肌强直的确定原因。肌肉兴奋性的这些等位基因疾病的表型变异的机制基础仍然未知。P1158S突变分离出一种非典型表型，即低温诱导的低钾性麻痹和高温下的肌强直。目的：本研究扩展了P1158S突变的功能特征，并验证了Na通道慢失活受损是周期性麻痹的共同特征这一特定假设。突变型NaV1.4通道（P1158S）在人胚肾细胞中瞬时表达，并通过Na电流的电压钳研究表征。野生型和P1158S通道在37 ℃下表现出相当的行为，但在冷却至25 ℃时，结论：与其他与麻痹表型相关的NaV1.4突变一致，P1158S突变破坏了慢失活。通道缺陷独特的温度敏感性可能导致不寻常的临床表型。
Background: Missense mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. The mechanistic basis for the phenotypic variability of these allelic disorders of muscle excitability remains unknown. An atypical phenotype with cold-induced hypokalemic paralysis and myotonia at warm temperatures was reported to segregate with the P1158S mutation.Objective: This study extends the functional characterization of the P1158S mutation and tests the specific hypothesis that impairment of Na channel slow inactivation is a common feature of periodic paralysis.Methods: Mutant NaV1.4 channels (P1158S) were transiently expressed in human embryonic kidney cells and characterized by voltage-clamp studies of Na currents.Results: Wild-type and P1158S channels displayed comparable behavior at 37 C, but upon cooling to 25 C, mutant channels activated at more negative potentials and slow inactivation was destabilized.Conclusions: Consistent with other NaV1.4 mutations associated with a paralytic phenotype, the P1158S mutation disrupts slow inactivation. The unique temperature sensitivity of the channel defect may contribute to the unusual clinical phenotype.