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Mammalian two-pore-channels (TPC1, 2;  TPCN1, TPCN2 ) are ubiquitously- expressed, PI(3,5)P 2 -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  Ly sosomal  Na  +  channel  V oltage-dependent  A ctivators (LyNa-VAs). We also identified another compound which, like PI(3,5)P 2 , activates TPC2 independent of voltage, suggesting the existence of agonist-specific gating mechanisms. Our identification of small-molecule TPC agonists should facilitate the studies of the cell biological roles of TPCs and can also readily explain the reported effects of TCAs in the modulation of autophagy and lysosomal functions.

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