PIP regulation of the TPC family. (A) Small region near the edge of a cell. Relative to the other PIPs, the plasma membrane has high concentrations of PI(4,5)P₂ (blue), and late endosomes have high concentrations of PI(3,5)P₂ (orange). (B) Expanded section of A illustrates the molecular details of PIP interactions with the TPCs. Channels open or close depending on association with their respective activating PIP. In subpanel 1, TPC1/2 are activated by the abundant PI(3,5)P₂ in late endosomes, but TPC3 is not activated by the PI(4,5)P₂ in the plasma membrane. After induction through a prolonged depolarization, subpanel 2 shows that PI(3,4)P₂ (yellow) is elevated in the plasma membrane. The transient fluctuation in PI(3,4)P₂ activates TPC3 by a “blip” type of regulation. The activation of TPC1/2 is determined only by the continued, local presence of PI(3,5)P₂, conforming to the “ZIP” code type of regulation.