Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder
Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder
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DOI：
10.1038/ng1585
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发表时间：
2005-07-01
期刊：
影响因子：
30.8
通讯作者：
Wang, QK
中科院分区：
文献类型：
--
作者：
Du, W;Bautista, JF;Wang, QK
大电导钙敏感钾（BK）通道在许多器官和组织中广泛表达，但其在体内的生理功能尚未完全明确。在此我们报道了一个位于10号染色体10q22区域与人类全身性癫痫和阵发性运动障碍共存综合征相关的基因位点，并表明BK通道的α亚基突变导致了该综合征。突变的BK通道具有明显更大的宏观电流。单通道记录显示，由于钙离子敏感性提高了3到5倍，开放通道的概率增加。我们提出，体内BK通道的增强通过诱导动作电位的快速复极化而导致兴奋性增加，从而通过使神经元以更快的速率放电而导致全身性癫痫和阵发性运动障碍。这些结果确定了一个在全身性癫痫和阵发性运动障碍中发生突变的基因，并对人类癫痫的发病机制、阵发性运动障碍的神经生理学以及BK通道在神经系统疾病中的作用具有重要意义。
The large conductance calcium- sensitive potassium ( BK) channel is widely expressed in many organs and tissues, but its in vivo physiological functions have not been fully defined. Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the a subunit of the BK channel causes this syndrome. The mutant BK channel had a markedly greater macroscopic current. Single- channel recordings showed an increase in open-channel probability due to a three- to fivefold increase in Ca2+ sensitivity. We propose that enhancement of BK channels in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate. These results identify a gene that is mutated in generalized epilepsy and paroxysmal dyskinesia and have implications for the pathogenesis of human epilepsy, the neurophysiology of paroxysmal movement disorders and the role of BK channels in neurological disease.