Drosophila TRPML Forms PI(3,5)P2-activated Cation Channels in Both Endolysosomes and Plasma Membrane

Abstract

Background: Drosophila trpml mutants reproduced many defects associated with mucolipidosis type IV, but the fly TRPML channel remains uncharacterized. Results: Drosophila TRPML is a phosphoinositide-regulated cation channel on endolysosome and plasma membranes. Conclusion: Fly TRPML largely resembles mammalian TRPML1, but exhibits differences in subcellular localization and pH dependence. Significance: The data support using Drosophila for assessing TRPML1 function.

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

“…A luminal linker domain forms a fenestrated canopy atop the channel, providing multiple luminal ion passages to the pore and also creating a negative electrostatic trap – preferably for divalent cations at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, providing structural implication for the S4-S5 linker-mediated PIP 2 gating mechanism among TRPML channels 7,8 . …”

“…TRPML1 is a Ca 2+ -permeable, non-selective, six-transmembrane (6-TM) tetrameric cation channel, and is believed to be the main lysosomal Ca 2+ release channel important for lysosomal trafficking and signal transduction 15-19 . Like most TRP channels, TRPML1 is ligand-gated and can be activated by the endolysosomal specific lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ) 7,8 , but is inhibited by the plasma membrane-localized phosphoinositide isoform PI(4,5)P 2 14 (Extended Data Fig. 1).…”

Insect TRP channels as targets for insecticides and repellents

“…26) While mutants of TRPML display severe neurodegeneration and motor deficits associated with impairment of autophagic removal of damaged mitochondria, as well as accumulation of lysosome vesicles, 27) it is unclear how rapidly these effects would incapacitate an insect if TRPML were attacked chemically.…”

Regulation of TRPML1 function

“…Drosophila trpml has also been found to be sensitive to PI(3,5)P 2 [25]. trpml was expressed in HEK293T cells, and found to be localized to endosomes and lysosomes.…”