TPCs: From plant to human

In 2005, the Arabidopsis thaliana two-pore channel TPC1 channel was identified as a vacuolar Ca^²⁺-release channel. In 2009 three independent groups published studies on mammalian TPCs as NAADP-activated endolysosomal Ca²⁺ release channels, results that were eventually challenged by two other groups, claiming mammalian TPCs to be PI(3,5)P₂ activated Na⁺ channels. By now this dispute seems to have been largely reconciled. Lipophilic small molecule agonists of TPC2, mimicking either the NAADP or the PI(3,5)P₂ mode of channel activation, revealed, together with structural evidence, that TPC2 can change its selectivity for Ca²⁺ versus Na⁺ in a ligand-dependent fashion (N- versus P-type activation). Furthermore, NAADP-binding proteins, JPT2 and Lsm12 were discovered, corroborating the hypothesis that NAADP activation of TPCs only works in the presence of these auxiliary NAADP-binding proteins. Pathophysiologically, loss or gain of function of TPCs has effects on autophagy, exocytosis, endocytosis, and intracellular trafficking, e.g., LDL cholesterol trafficking leading to fatty liver disease or viral and bacterial toxin trafficking, corroborating roles of TPCs in infectious diseases such as Ebola or Covid19. Defects in trafficking of EGFR and 1-integrin suggested roles in cancer. In neurodegenerative lysosomal storage disease models, P-type activation of TPC2 was found to have beneficial effects on both in vitro and in vivo hallmarks of Niemann- Pick disease type C1, Batten disease, and Mucolipidosis type IV. Here, we cover the latest on structure, function, physiology, and pathophysiology of these channels with a focus initially on plant followed by mammalian TPCs, and we discuss their potential as drug targets, including currently available pharmacology.