TY - JOUR TI - Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ channels AU - Zhang, Xiaoli AU - Chen, Wei AU - Li, Ping AU - Calvo, Raul AU - Southall, Noel AU - Hu, Xin AU - Bryant-Genevier, Melanie AU - Feng, Xinghua AU - Geng, Qi AU - Gao, Chenlang AU - Yang, Meimei AU - Tang, Kaiyuan AU - Ferrer, Marc AU - Marugan, Juan Jose AU - Xu, Haoxing A2 - Islas, Leon D A2 - Aldrich, Richard W A2 - Islas, Leon D A2 - Muallem, Shmuel A2 - Brelidze, Tinatin VL - 8 PY - 2019 DA - 2019/12/11 SP - e51423 C1 - eLife 2019;8:e51423 DO - 10.7554/eLife.51423 UR - https://doi.org/10.7554/eLife.51423 AB - 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 Activators (LyNa-VAs). We also identified another compound which, like PI(3,5)P2, 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. KW - lysosomal two-pore channels KW - tri-cyclic antidepressants KW - whole-endolysosome patch clamp KW - lysosomal Na+ channels JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -