Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.
Pharmacol Ther. 2021 Apr;220:107713. doi: 10.1016/j.pharmthera.2020.107713. Epub 2020 Oct 24.
The old Greek saying "Panta Rhei" ("everything flows") is true for all life and all living things in general. It also becomes nicely evident when looking closely into cells. There, material from the extracellular space is taken up by endocytic processes and transported to endosomes where it is sorted either for recycling or degradation. Cargo is also packaged for export through exocytosis involving the Golgi network, lysosomes and other organelles. Everything in this system is in constant motion and many proteins are necessary to coordinate transport along the different intracellular pathways to avoid chaos. Among these proteins are ion channels., in particular TRPML channels (mucolipins) and two-pore channels (TPCs) which reside on endosomal and lysosomal membranes to speed up movement between organelles, e.g. by regulating fusion and fission; they help readjust pH and osmolarity changes due to such processes, or they promote exocytosis of export material. Pathophysiologically, these channels are involved in neurodegenerative, metabolic, retinal and infectious diseases, cancer, pigmentation defects, and immune cell function, and thus have been proposed as novel pharmacological targets, e.g. for the treatment of lysosomal storage disorders, Duchenne muscular dystrophy, or different types of cancer. Here, we discuss the similarities but also differences of TPCs and TRPMLs in regulating phagocytosis, autophagy and lysosomal exocytosis, and we address the contradictions and open questions in the field relating to the roles TPCs and TRPMLs play in these different processes.
对于所有的生命和生物来说，古希腊的谚语“一切皆流”（Panta Rhei）都是正确的。当我们仔细观察细胞时，这一点变得非常明显。在细胞中，细胞外空间的物质通过内吞作用被吸收，并被运输到内涵体，在那里它被分类为回收或降解。货物也通过涉及高尔基体网络、溶酶体和其他细胞器的胞吐作用进行包装，以便出口。这个系统中的一切都在不断运动，许多蛋白质是协调沿着不同的细胞内途径运输所必需的，以避免混乱。这些蛋白质包括离子通道，特别是 TRPML 通道（粘脂素）和双孔通道（TPCs），它们位于内涵体和溶酶体膜上，以加速细胞器之间的运动，例如通过调节融合和裂变；它们有助于因这些过程而导致的 pH 值和渗透压变化的调整，或者促进出口物质的胞吐作用。从病理生理学上讲，这些通道参与神经退行性疾病、代谢疾病、视网膜疾病和传染病、癌症、色素沉着缺陷以及免疫细胞功能，因此被提议作为新的药理学靶点，例如用于治疗溶酶体贮积症、杜氏肌营养不良症或不同类型的癌症。在这里，我们讨论了 TPCs 和 TRPMLs 在调节吞噬作用、自噬和溶酶体胞吐作用方面的相似之处，但也存在差异，并解决了该领域中与 TPCs 和 TRPMLs 在这些不同过程中所扮演的角色相关的矛盾和未解决的问题。
