Two-pore channel blockade by phosphoinositide kinase inhibitors YM201636 and PI-103 determined by a histidine residue near pore-entrance.

ABSTRACT: Human two-pore channels (TPCs) are endolysosomal cation channels and play an important role in NAADP-evoked Ca²⁺ release and endomembrane dynamics. We found that YM201636, a PIKfyve inhibitor, potently inhibits PI(3,5)P₂-activated human TPC2 with an IC₅₀ of 0.16 μM. YM201636 also effectively inhibits NAADP-activated TPC2 and a constitutively-open TPC2 L690A/L694A mutant channel; whereas it exerts little effect when applied in the channel's closed state. PI-103, a YM201636 analog and an inhibitor of PI3K and mTOR, also inhibits human TPC2 with an IC₅₀ of 0.64 μM. With mutational, virtual docking, and molecular dynamic simulation analyses, we found that YM201636 and PI-103 directly block the TPC2's open-state channel pore at the bundle-cross pore-g

SUBMITTER: Du C 

PROVIDER: S-EPMC9308409 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature