Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
CNS Neurol Disord Drug Targets. 2018;17(4):261-266. doi: 10.2174/1871527317666180202110717.
BACKGROUND & OBJECTIVE: The lysosome is a membrane-enclosed organelle widely found in every eukaryotic cell. It has been deemed as the stomach of the cells. Recent studies revealed that it also functions as an intracellular calcium store and is a platform for nutrient-dependent signal transduction. Similar with the plasma membrane, the lysosome membrane is furnished with various proteins, including pumps, ion channels and transporters. So far, two types of lysosomal potassium channels have been identified: large-conductance and Ca2+-activated potassium channel (BK) and TMEM175. TMEM175 has been linked to several neurodegeneration diseases, such as the Alzheimer and Parkinson disease. Recent studies showed that TMEM175 is a lysosomal potassium channel with novel architecture and plays important roles in setting the lysosomal membrane potential and maintaining pH stability. TMEM175 deficiency leads to compromised lysosomal function, which might be responsible for the pathogenesis of related diseases. BK is a well-known potassium channel for its function on the plasma membrane. Studies from two independent groups revealed that functional BK channels are also expressed on the lysosomal plasma membrane. Dysfunction of BK causes impaired lysosomal calcium signaling and abnormal lipid accumulation, a featured phenotype of most lysosomal storage diseases (LSDs). Boosting BK activity could rescue the lipid accumulation in several LSD cell models. Overall, the lysosomal potassium channels are essential for the lysosome physiological function, including lysosomal calcium signaling and autophagy. The dysfunction of lysosomal potassium channels is related to some neurodegeneration disorders.
Therefore, lysosomal potassium channels are suggested as potential targets for the intervention of lysosomal disorders.
溶酶体是一种广泛存在于真核细胞中的膜结合细胞器，被认为是细胞的“胃”。最近的研究表明，它还充当细胞内钙库，并作为营养依赖性信号转导的平台。与质膜相似，溶酶体膜配备有各种蛋白质，包括泵、离子通道和转运体。迄今为止，已经鉴定出两种溶酶体钾通道：大电导和 Ca2+激活钾通道（BK）和 TMEM175。TMEM175 与几种神经退行性疾病有关，如阿尔茨海默病和帕金森病。最近的研究表明，TMEM175 是一种具有新型结构的溶酶体钾通道，在设定溶酶体膜电位和维持 pH 稳定性方面发挥重要作用。TMEM175 缺乏会导致溶酶体功能受损，这可能是相关疾病发病机制的原因。BK 是一种众所周知的质膜钾通道，其功能与其相关。两个独立的研究小组的研究表明，功能性 BK 通道也表达在溶酶体质膜上。BK 的功能障碍会导致溶酶体钙信号受损和异常脂质积累，这是大多数溶酶体贮积病（LSD）的特征表型。提高 BK 的活性可以挽救几种 LSD 细胞模型中的脂质积累。总的来说，溶酶体钾通道对于溶酶体的生理功能，包括溶酶体钙信号和自噬，是必不可少的。溶酶体钾通道的功能障碍与一些神经退行性疾病有关。
因此，溶酶体钾通道被认为是溶酶体疾病干预的潜在靶点。
