Issue Archive

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

Received: 2020-03-01　　Accepted: 2020-06-05

Corresponding author: 冯兴华　　E-mail: mnfxh@zjut.edu.cn

DOI: 10.13294/j.aps.2020.0095

Citing This Article：

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).