BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release
BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release
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DOI：
10.1016/j.devcel.2015.04.010
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发表时间：
2015-05-26
影响因子：
11.8
通讯作者：
Dong, Xian-Ping
中科院分区：
文献类型：
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作者：
Cao, Qi;Zhong, Xi Zoe;Dong, Xian-Ping
促进溶酶体运输代表了溶酶体贮积病的有希望的治疗方法。有效的Ca 2+从溶酶体的动员是重要的溶酶体运输。在缺乏反离子流的情况下，溶酶体的Ca 2+释放可在管腔中产生负电位，以干扰随后的Ca 2+释放。在这里，我们报告说，溶酶体表达大电导钙激活钾（BK）通道，形成物理和功能耦合与溶酶体钙释放通道，TRPML 1。通过TRPML 1的Ca 2+释放导致BK活化，这反过来又进一步促进溶酶体Ca 2+释放和膜运输。重要的是，BK过表达挽救了尼曼-匹克C1患者细胞中TRPML 1介导的Ca 2+释放受损和溶酶体蓄积异常。因此，我们已经确定了一个溶酶体K+通道，提供了一个正反馈机制，以促进TRPML 1介导的Ca 2+释放和膜运输。我们的研究结果表明，上调BK可能是一种潜在的治疗策略，某些溶酶体贮积病和常见的神经退行性疾病。
Promoting lysosomal trafficking represents a promising therapeutic approach for lysosome storage diseases. Efficient Ca2+ mobilization from lysosomes is important for lysosomal trafficking. Ca2+ release from lysosomes could generate a negative potential in the lumen to disturb subsequent Ca2+ release in the absence of counter ion flux. Here we report that lysosomes express big-conductance Ca2+-activated potassium (BK) channels that form physical and functional coupling with the lysosomal Ca2+ release channel, TRPML1. Ca2+ release via TRPML1 causes BK activation, which in turn facilitates further lysosomal Ca2+ release and membrane trafficking. Importantly, BK overexpression rescues the impaired TRPML1-mediated Ca2+ release and abnormal lysosomal storage in cells from Niemann-Pick C1 patients. Therefore, we have identified a lysosomal K+ channel that provides a positive feedback mechanism to facilitate TRPML1-mediated Ca2+ release and membrane trafficking. Our findings suggest that upregulating BK may be a potential therapeutic strategy for certain lysosomal storage diseases and common neurodegenerative disorders.