Mutant Channels Contribute Ͻ50% to Na Ϩ Current in Paramyotonia Congenita Muscle
Mutant Channels Contribute Ͻ50% to Na Ϩ Current in Paramyotonia Congenita Muscle
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先天性副肌强直中突变通道对 Na 电流贡献 Ͻ50%
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通讯作者：
H. Lerche
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作者：
N. Mitrović;Alfred L. George;Reinhardt Rü Del;F. Lehmann‐Horn;H. Lerche
在显性遗传疾病如通道病的病理生理学中的一个重要问题是突变蛋白的表达水平。在我们的研究中，我们解决了这个问题，通过比较门控缺陷的两个人肌肉Na+通道突变体（R1448 C和R1448 P）造成先天性副肌强直的天然肌肉标本从两个病人的相同的突变重组通道表达在人胚肾（HEK-293）细胞。转染HEK-293细胞的膜片钳记录显示，与野生型通道相比，突变体的Na+电流衰减明显减慢，稳态失活的左移和电压依赖性降低，通道重新开放的频率增加。
An important question in the pathophysiology of dominantly inherited diseases, such as channelopathies, is the level of expression of the mutant protein. In our study, we address this issue by comparing the gating defects of two human muscle Na ⍣ channel mutants (R1448C and R1448P) causing paramyotonia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney (HEK-293) cells. Patch-clamp recordings of transfected HEK-293 cells revealed a pronounced slowing of the Na ⍣ current decay, a left-shifted and decreased voltage dependence of steady-state inactivation, and an increased frequency of channel reopenings for mutant compared with wild-type channels.