Ionic Mechanisms of Two-Pore Channel Regulation of Vesicle Trafficking

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.