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This research examines the role of two-pore channels in regulating ion fluxes during endolysosomal trafficking.

January 22, 2026Cells0 citationsOpen Access

Ionic Mechanisms of Two-Pore Channel Regulation of Vesicle Trafficking

HZHeng ZhangNortheast Normal University MZMichael X. ZhuShenzhen Bay Laboratory

Key Points

This research examines the role of two-pore channels in regulating ion fluxes during endolysosomal trafficking.
Analyzed the function of TPC1 and TPC2 channels in endosomes and lysosomes.
Investigated the response of these channels to NAADP and PI(3,5)P2.
Explored calcium and sodium release mechanisms from acidic organelles.
Two-pore channels facilitate calcium and sodium release in endolysosomal membranes.
Regulated ion fluxes are essential for proper endosomal sorting and trafficking.
Dysfunction of TPCs may impact physiological and pathophysiological processes.

Abstract

The endolysosomal system plays a pivotal role in cellular function. Before reaching lysosomes for degradation, the endocytosed cargoes are sorted at various stages of endosomal trafficking for recycling and/or rerouting. The proper execution of these processes depends on tightly regulated ion fluxes across endolysosomal membranes. Recent studies have demonstrated the importance of two-pore channels (TPCs), including TPC1 and TPC2, in endolysosomal trafficking. These channels are expressed in the membranes of distinct populations of endosomes and lysosomes, where they respond to nicotinic acid adenine dinucleotide phosphate (NAADP) and phosphatidylinositol 3,5-bisphosphate PI(3,5)P2 to conduct Ca2+ and Na+ release from these acidic organelles. Here, we discuss the potential implications of Ca2+ and Na+ fluxes mediated by TPCs across endolysosomal membranes in the physiological and pathophysiological functions of these organellar channels.

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