Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalaemic periodic paralysis type II

被引:55
作者
Kuzmenkin, A
Muncan, V
Jurkat-Rott, K
Hang, C
Lerche, H
Lehmann-Horn, F
Mitrovic, N [1 ]
机构
[1] Univ Ulm, Dept Appl Physiol, D-89069 Ulm, Germany
[2] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany
关键词
channelopathies; paralysis; patch-clamp; S4; segment; voltage sensor;
D O I
10.1093/brain/awf071
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Hypokalaemic periodic paralysis (hypoPP) is a dominantly inherited muscle disorder characterized by episodes of flaccid weakness. Previous genetic studies revealed mutations in the voltage-gated calcium channel alpha1-subunit (CACNA1S gene) in families with hypoPP (type I). Electrophysiological studies on these mutants in different expression systems could not explain the pathophysiology of the disease. In addition, several mutations (Arg669His, Arg672His, Arg672Gly and Arg672Ser) in the voltage sensor of the skeletal muscle sodium channel alpha-subunit (SCN4A gene) have been found in families with hypoPP (type II). For Arg672Gly/His a fast inactivation defect was described, and for Arg669His an impairment of slow inactivation was reported. Except for the substitution for serine, we have now expressed all mutants in a human cell-line and studied them electrophysiologically. Patch-clamp recordings show an enhanced fast inactivation for all three mutations, whereas two of them reveal enhanced slow inactivation. This may reduce the number of functional sodium channels at resting membrane potential and contribute to the long-lasting periods of paralysis experienced by hypoPP patients. The gating of both histidine mutants (Arg669His, Arg672His) can be modulated by changes of extra- or intracellular pH. The inactivation defects of Arg669His and Arg672His can be alleviated by low pH to a significant degree, suggesting that the decrease of pH in muscle cells (e.g. during muscle work) might lead to an auto-compensation of functional defects. This may explain a delay or prevention of paralytic attacks in patients by slight physical activity. Moreover, the histidine residues may be the target for a potential therapeutic action by acetazolamide.
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收藏
页码:835 / 843
页数:9
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