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

Pitt, Samantha J.; Lam, Andy K. M.; Rietdorf, Katja; Galione, Antony and Sitsapesan, Rebecca (2014). Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+. Science Signaling, 7(326), article no. ra46.

DOI (Digital Object Identifier) Link: https://doi.org/10.1126/scisignal.2004854
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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 Ca<Sup>2+</sup> 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.

Item Type: Journal Item
Copyright Holders: 2014 The Authors
ISSN: 1937-9145
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetBHF
Not SetNot SetWellcome Trust
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 40588
Depositing User: Katja Rietdorf
Date Deposited: 22 Jul 2014 15:55
Last Modified: 22 May 2019 10:16
URI: http://oro.open.ac.uk/id/eprint/40588
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