Function and dysfunction of two-pore channels.

Two-pore channels (TPCs) are evolutionarily important members of the voltage-gated ion channel superfamily. TPCs localize to acidic Ca(2+) stores within the endolysosomal system. Most evidence indicate that TPCs mediate Ca(2+) signals through the Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) to control a range of Ca(2+)-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 Ca(2+) 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.