Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?
Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?
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溶酶体离子通道：它们有什么用处以及它们是可药物靶标吗？
DOI：
10.1146/annurev-pharmtox-051921-013755
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发表时间：
2022
影响因子：
12.5
通讯作者：
Dejian Ren
中科院分区：
文献类型：
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作者：
Erika A. Riederer;Chunlei Cang;Dejian Ren
溶酶体在物质消化、细胞清除、再循环、胞吐作用、伤口修复、Ca 2+信号传导、营养信号传导和基因表达调控中发挥重要作用。细胞器还充当涉及mTOR和AKT激酶的重要信号网络的枢纽。在过去的十年中，电生理记录和分子和结构研究已经发现了几种独特的溶酶体离子通道和转运蛋白，包括TPC、TMEM 175、TRPML、CLN 7和CLC-7。它们是细胞器对主要离子（包括K+、Na+、H+、Ca 2+和Cl-）的渗透性的基础。这些通道受许多细胞因子调节，从腔中的H+和穿过溶酶体膜的电压到胞质溶胶中的ATP到细胞外的生长因子。通道/转运蛋白基因的遗传变异与包括溶酶体贮积病和神经退行性疾病在内的疾病相关。最近对人类遗传学和通道激活剂的研究表明，溶酶体通道可能是开发用于预防和干预人类疾病的治疗剂的有吸引力的靶标。药理学和毒理学年度评论第63卷的预期最终在线出版日期为2023年1月。请访问http://www.annualreviews.org/page/journal/pubdates了解修订后的估计数。
Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca2+ signaling, nutrient signaling, and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR and AKT kinases. Electrophysiological recording and molecular and structural studies in the past decade have uncovered several unique lysosomal ion channels and transporters, including TPCs, TMEM175, TRPMLs, CLN7, and CLC-7. They underlie the organelle's permeability to major ions, including K+, Na+, H+, Ca2+, and Cl-. The channels are regulated by numerous cellular factors, ranging from H+ in the lumen and voltage across the lysosomal membrane to ATP in the cytosol to growth factors outside the cell. Genetic variations in the channel/transporter genes are associated with diseases that include lysosomal storage diseases and neurodegenerative diseases. Recent studies with human genetics and channel activators suggest that lysosomal channels may be attractive targets for the development of therapeutics for the prevention of and intervention in human diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.