Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2. Five things to know

Two-pore channels are ancient members of the voltage-gated ion channel superfamily that are expressed predominantly on acidic organelles such as endosomes and lysosomes. Here we review recent advances in understanding how TPCs are activated by their ligands and identify five salient features: (1) TPCs are Ca2+-permeable non-selective cation channels gated by NAADP. (2) NAADP activation is indirect through associated NAADP receptors. (3) TPCs are also Na+-selective channels gated by PI(3,5)P-2. (4) PI(3,5)P-2 activation is direct through a structurally-resolved binding site. (5) TPCs switch their ion selectivity in an agonist-dependent manner.

Automated summary

Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that are primarily found on acidic organelles. TPCs can be activated by ligands and have calcium and sodium permeability, with the ability to switch their ion selectivity in response to specific agonists.