ReviewCell Biology

Function and dysfunction of two-pore channels

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Sci. Signal.  07 Jul 2015:
Vol. 8, Issue 384, pp. re7
DOI: 10.1126/scisignal.aab3314

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Gloss

Two-pore channels (TPCs) are localized to the endolysosomal system, where they function as ion channels that likely conduct Ca2+, Na+, and H+. These channels drive trafficking of cargo through the endolysosomal system, and dysregulation of this trafficking may contribute to disorders, such as Parkinson’s disease, fatty liver disease, and Ebola infection. This Review with 3 figures and 96 references describes the history, function, controversy, and pathophysiology of these important intracellular channels.

Abstract

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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