[The new target of Rapamycin: lysosomal calcium channel TRPML1]

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Rapamycin (Rap) is an immunosuppressant with potential anticancer, neuroprotective, and anti-aging applications.
• Rapamycin's canonical mechanism involves inhibiting mammalian target of Rap (mTOR), which affects autophagy and lysosomal function via ULK1 and transcription factor EB (TFEB).

Purpose of the Study:

• To review the established Rapamycin-mTOR-ULK1/TFEB pathway.
• To discuss the newly discovered Rapamycin-TRPML1-Calcineurin-TFEB pathway and its pharmacological implications.

Main Methods:

• Literature review of Rapamycin's mechanisms of action.
• Analysis of signaling pathways involving mTOR, TRPML1, Calcineurin, and TFEB.

Main Results:

• Rapamycin directly activates the lysosomal cation channel TRPML1 independently of mTOR.
• TRPML1 activation leads to lysosomal calcium release, sensed by Calcineurin.
• Calcineurin activation of TFEB enhances lysosomal function and autophagy.

Conclusions:

• The discovery of the Rapamycin-TRPML1 pathway broadens understanding of Rapamycin's pharmacological roles.
• This novel pathway presents new therapeutic targets for diseases involving lysosomal dysfunction and autophagy.