title: Two-pore channels at the intersection of endolysosomal membrane traffic.
abstract: Two-pore channels (TPCs) are ancient members of the voltage-gated ion channel superfamily that localize to acidic organelles such as lysosomes. The TPC complex is the proposed target of the Ca2+-mobilizing messenger NAADP, which releases Ca2+ from these acidic Ca2+ stores. Whereas details of TPC activation and native ion permeation remain unclear, a consensus has emerged around their function in regulating endolysosomal trafficking. This role is supported by recent proteomic data showing that TPCs interact with proteins controlling membrane organization and dynamics, including Rab GTPases and components of the fusion apparatus. Regulation of TPCs by PtdIns(3,5)P2 and/or NAADP (nicotinic acid adenine dinucleotide phosphate) together with their functional and physical association with Rab proteins provides a mechanism for coupling phosphoinositide and trafficking protein cues to local ion fluxes. Therefore, TPCs work at the regulatory cross-roads of (patho)physiological cues to co-ordinate and potentially deregulate traffic flow through the endolysosomal network. This review focuses on the native role of TPCs in trafficking and their emerging contributions to endolysosomal trafficking dysfunction.
authors.affiliation: *Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, U.S.A.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Marchant
authors.affiliation: †Department of Cell and Developmental Biology, University College London, London WC1E 6BT, U.K.
authors.forename: Sandip
authors.initials: S
authors.lastname: Patel
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D009249:NADP / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D009249:NADP; C024376:NAADP; D020691:rab GTP-Binding Proteins; D002118:Calcium