Department of Physiology and Pharmacology, The Libin Cardiovascular Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Sci Rep. 2013;3:2447. doi: 10.1038/srep02447.
Large-conductance, calcium-activated-K(+) (BK) channels are widely distributed throughout the nervous system, where they regulate action potential duration and firing frequency, along with presynaptic neurotransmitter release. Our recent efforts to identify chaperones that target neuronal ion channels have revealed cysteine string protein (CSPα) as a key regulator of BK channel expression and current density. CSPα is a vesicle-associated protein and mutations in CSPα cause the hereditary neurodegenerative disorder, adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL). CSPα null mice show 2.5 fold higher BK channel expression compared to wild type mice, which is not seen with other neuronal channels (i.e. Cav2.2, Kv1.1 and Kv1.2). Furthermore, mutations in either CSPα's J domain or cysteine string region markedly increase BK expression and current amplitude. We conclude that CSPα acts to regulate BK channel expression, and consequently CSPα-associated changes in BK activity may contribute to the pathogenesis of neurodegenerative disorders, such as ANCL.
大电导、钙激活钾 (BK) 通道广泛分布于神经系统，调节动作电位持续时间和放电频率，以及突触前神经递质释放。我们最近努力鉴定靶向神经元离子通道的伴侣蛋白，发现半胱氨酸拉链蛋白 (CSPα) 是 BK 通道表达和电流密度的关键调节因子。CSPα 是囊泡相关蛋白，CSPα 突变导致遗传性神经退行性疾病，成人发病常染色体显性神经元蜡样脂褐质沉积症 (ANCL)。CSPα 敲除小鼠的 BK 通道表达比野生型小鼠高 2.5 倍，而其他神经元通道（即 Cav2.2、Kv1.1 和 Kv1.2）则没有这种现象。此外，CSPα 的 J 结构域或半胱氨酸拉链区的突变显著增加 BK 表达和电流幅度。我们得出结论，CSPα 调节 BK 通道表达，因此与 CSPα 相关的 BK 活性变化可能导致神经退行性疾病的发病机制，如 ANCL。
