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

eLife - Tập 8
Xiaoli Zhang1, W. Chen1, Ping Li2,1, Raul Calvo3, Noel Southall3, Xin Hu3, Melanie Bryant‐Genevier3, Xinghua Feng2, Qi Geng1, Chenlang Gao1, Meimei Yang1,4, Kaiyuan Tang1, Marc Ferrer3, Juan Marugán3, Haoxing Xu1
1Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
2Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, China
3National Center for Advancing Translational Sciences (NCATS), Medical Center Drive, Rockville, United States
4Department of Neurology, The Fourth Hospital of Harbin Medical University, Harbin, China

Tóm tắt

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.

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Tập 8

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