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Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+

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Author(s)

Samantha J Pitt, Andy K M Lam, Katja Rietdorf, Antony Galione, Rebecca Sitsapesan

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Abstract

NAADP potently triggers Ca2+ release from acidic lysosomal and endolysosomal Ca2+stores. Human two-pore channels (TPC1 and TPC2), which are located on
these stores, are involved in this process, but there is controversy over whether TPC1 and TPC2 constitute the Ca2+ release channels. We therefore examined the single-channel properties of human TPC1 after reconstitution into bilayers of controlled composition. We found that TPC1 was permeable not only to Ca2+ but also to monovalent cations and that permeability to protons was the highest (relative permeability sequence: H+ >> K+ > Na+ ≥ Ca2+). NAADP or Ca2+
activated TPC1, and the presence of one of these ligands was required for channel activation. The endolysosome-located lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] had no effect on TPC1 open probability but significantly increased the relative permeability of Na+ to Ca2+ and of H+ to Ca2+.
Furthermore, our data showed that, although both TPC1 and TPC2 are
stimulated by NAADP, these channels differ in ion selectivity and modulation by Ca2+ and pH. We propose that NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+-releasing ability of TPC1 will depend on the ionic composition of the acidic stores and may be influenced by other regulators that affect TPC1 ion permeation.

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Details

Original languageEnglish
Article numberra46
JournalScience Signaling
Volume7
Issue number326
DOIs
Publication statusPublished - 20 May 2014

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