Two-pore channels (TPCs) are evolutionarily important members of the voltage-gated ion channel superfamily. TPCs localize to acidic Ca2+ stores within the endolysosomal system. Most evidence indicate that TPCs mediate Ca2+ signals through the Ca2+-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) to control a range of Ca2+-dependent events. Recent studies clarify the mechanism of TPC activation and identify roles for TPCs in disease, highlighting the regulation of endolysosomal membrane traffic by local Ca2+ fluxes. Chemical targeting of TPCs to maintain endolysosomal “well-being” may be beneficial in disorders as diverse as Parkinson’s disease, fatty liver disease, and Ebola virus infection.
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