TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes

Cell. 2012 Oct 12;151(2):372-83. doi: 10.1016/j.cell.2012.08.036.


Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P(2) and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na(+), not K(+), as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P(2) in regulating the fusogenic potential of intracellular organelles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cell Line
  • Glucose / metabolism
  • Insulin-Secreting Cells / metabolism
  • Islets of Langerhans / metabolism
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • NADP / analogs & derivatives
  • NADP / metabolism
  • Phosphatidylinositol Phosphates / metabolism*
  • Sodium Channels / metabolism


  • Calcium Channels
  • Phosphatidylinositol Phosphates
  • Sodium Channels
  • TPCN1 protein, mouse
  • TPCN2 protein, mouse
  • NADP
  • Glucose
  • Calcium