Skip to content

Research at St Andrews

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

Research output: Contribution to journalArticle

Author(s)

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

School/Research organisations

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.

Close

Details

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

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Plasma non-esterified fatty acids contribute to increased coagulability in type-2 diabetes through altered plasma zinc speciation

    Sobczak, A. I. S., Katundu, K. G. H., Phoenix, F. A., Khazaipoul, S., Yu, R., Lampiao, F., Stefanowicz, F., Blindauer, C. A., Pitt, S. J., Smith, T. K., Ajjan, R. A. & Stewart, A. J., 28 Aug 2019, In : biorxiv. 38 p.

    Research output: Contribution to journalArticle

  2. Total plasma magnesium, zinc, copper and selenium concentrations in type-I and type-II diabetes

    Sobczak, A. I. S., Stefanowicz, F., Pitt, S. J., Ajjan, R. A. & Stewart, A. J., Feb 2019, In : BioMetals. 32, 1, p. 123-138 16 p.

    Research output: Contribution to journalArticle

  3. FUNCTIONAL CHARACTERIZATION OF ATP2C2, A RISK FACTOR FOR LANGUAGE DISORDERS

    Martinelli, A., Diaz, R., Feliciotti, I., Pitt, S. & Paracchini, S., 2019, In : European Neuropsychopharmacology. 29, p. 1194-1195 2 p.

    Research output: Contribution to journalAbstract

  4. Influence of zinc on glycosaminoglycan neutralisation during coagulation

    Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J., Sep 2018, In : Metallomics. 10, 9, p. 1180-1190 11 p.

    Research output: Contribution to journalReview article

  5. Glycosaminoglycan neutralization in coagulation control

    Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J., Jun 2018, In : Arteriosclerosis, Thrombosis, and Vascular Biology. 38, 6, p. 1258-1270 14 p.

    Research output: Contribution to journalReview article

Related by journal

  1. Generation of specific inhibitors of SUMO1- and SUMO2/3-mediated protein-protein interactions using Affimer (Adhiron) technology

    Hughes, D. J., Tiede, C., Penswick, N., A. S. Tang, A., Trinh, C. H., Mendal, U., Zajac, K. Z., Gaule, T., Howell, G., Edwards, T. A., Duan, J., Feyfant, E., McPhereson, M. J., Tomlinson, D. C. & Whitehouse, A., 14 Nov 2017, In : Science Signaling. 10, 505, 14 p., eaaj2005.

    Research output: Contribution to journalArticle

  2. Isolation of isoform-specific binding proteins (Affimers) by phage display using negative selection

    Tang, A. A-S., Tiede, C., Hughes, D. J., McPherson, M. J. & Tomlinson, D. C., 14 Nov 2017, In : Science Signaling. 10, 505, 12 p., eaan0868.

    Research output: Contribution to journalArticle

ID: 120977651