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雷帕霉素的新靶点: 溶酶体钙离子通道TRPML1

黎倩¹, 蔡伟杰¹, 吉永华^2,3, 冯兴华^1,*

¹浙江工业大学长三角绿色制药协同创新中心，杭州 310014；²上海大学生物膜与生物医药研究所，上海 200444；³上海新华医院崇明分院癌痛转化医学研究所，上海 202150

摘要

雷帕霉素(Rapamycin, Rap)是一种免疫抑制剂，在临床上主要应用于器官移植过程中的抗排异反应，同时，Rap在抗癌、神经保护和抗衰老等领域也展现出巨大潜力。通过抑制哺乳动物Rap靶蛋白(mammalian target of Rapamycin, mTOR)活性，Rap能够活化调节溶酶体功能的转录因子EB (transcription factor EB, TFEB)从而上调溶酶体功能，同时，Rap也能够去除mTOR对ULK1 (unc-51 like autophagy activating kinase 1)的抑制效果从而促进自噬。最新研究显示，Rap能够直接激活溶酶体钙离子通道TRPML1，此效应并不依赖于mTOR；TRPML1通道的开放可释放溶酶体钙离子，钙调神经磷酸酶(Calcineurin)作为此溶酶体来源的钙信号的感受器活化TFEB，进而增强溶酶体功能并促进自噬。此发现拓宽了对Rap药理学机制的认知，为衰老等领域的机制研究提供了理论基础。本文将以经典的Rap-mTOR-ULK1/TFEB信号通路为导引，详细介绍溶酶体钙离子通道TRPML1被确认为Rap新靶标的论证过程，并简要讨论此新信号通路(Rap-TRPML1-Calcineurin-TFEB)的药理学意义。

关键词： 雷帕霉素; 哺乳动物雷帕霉素靶蛋白; ULK1; TRPML1; 转录因子EB; 自噬

分类号：R9

The new target of Rapamycin: lysosomal calcium channel TRPML1

LI Qian¹, CAI Wei-Jie¹, JI Yong-Hua^2,3, FENG Xing-Hua^1,*

¹Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China；²Institute of Biofilm and Biomedicine, Shanghai University, Shanghai 200444, China；³Institute of Translational Medicine for Cancer Pain, Chongming Branch, Shanghai Xinhua Hospital, Shanghai 202150, China

Abstract

Rapamycin (Rap) is an immunosuppressant, which is mainly used in the anti-rejection of organ transplantation. Meanwhile, it also shows great potential in the fields of anticancer, neuroprotection and anti-aging. Rap can inhibit the activity of mammalian target of Rap (mTOR). It activates the transcription factor EB (TFEB) to up-regulate lysosomal function and eliminates the inhibitory effect of mTOR on ULK1 (unc-51 like autophagy activating kinase 1) to promote autophagy. Recent research showed that Rap can directly activate the lysosomal cation channel TRPML1 in an mTOR-independent manner. TRPML1 activation releases lysosomal calcium. Calcineurin functions as the sensor of the lysosomal calcium signal and activates TFEB, thus promoting lysosome function and autophagy. This finding has greatly broadened and deepened our understanding of the pharmacological roles of Rap. In this review, we briefly introduce the canonical Rap-mTOR-ULK1/TFEB signaling pathway, and then discuss the discovery of TRPML1 as a new target of Rap and the pharmacological potential of this novel Rap-TRPML1-Calcineurin-TFEB pathway.

Key words: Rapamycin; mammalian target of Rapamycin; ULK1; TRPML1; transcription factor EB; autophagy

收稿日期：2020-03-01　　录用日期：2020-06-05

通讯作者：冯兴华　　E-mail: mnfxh@zjut.edu.cn

DOI: 10.13294/j.aps.2020.0095

引用本文：

黎倩, 蔡伟杰, 吉永华, 冯兴华. 雷帕霉素的新靶点: 溶酶体钙离子通道TRPML1[J]. 生理学报 2021; 73 (1): 137-142.

LI Qian, CAI Wei-Jie, JI Yong-Hua, FENG Xing-Hua. The new target of Rapamycin: lysosomal calcium channel TRPML1. Acta Physiol Sin 2021; 73 (1): 137-142 (in Chinese with English abstract).