Agonist-specific voltage-dependent gating of lysosomal two-pore Na⁺ channels.

ABSTRACT: Mammalian two-pore-channels (TPC1, 2; TPCN1, TPCN2) are ubiquitously- expressed, PI(3,5)P₂-activated, Na⁺-selective channels in the endosomes and lysosomes that regulate luminal pH homeostasis, membrane trafficking, and Ebola viral infection. Whereas the channel activity of TPC1 is strongly dependent on membrane voltage, TPC2 lacks such voltage dependence despite the presence of the presumed 'S4 voltage-sensing' domains. By performing high-throughput screening followed by lysosomal electrophysiology, here we identified a class of tricyclic anti-depressants (TCAs) as small-molecule agonists of TPC channels. TCAs activate both TPC1 and TPC2 in a voltage-dependent manner, referred to as Lysosomal Na⁺ channel Voltage-dependent

SUBMITTER: Zhang X 

PROVIDER: S-EPMC6905855 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature