TPC Proteins Are Phosphoinositide- Activated Sodium-Selective Ion Channels in Endosomes and Lysosomes

SummaryMammalian 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)P2 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)P2 in regulating the fusogenic potential of intracellular organelles.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (271 K)Download as PowerPoint slideHighlights► TPC proteins are sodium-selective channels in the lysosome ► Two-pore channels are activated specifically by PI(3,5)P2 ► Two-pore channels are not NAADP receptors ► Lysosomes are high-sodium compartments