ArticleScience signaling2014
Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+.
Article in Science signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 85 citations in OpenAlex.
- TPC1-dependent control of endosomal pH and transferrin uptake determines cellular iron status.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Endosomal TPC1-mediated CaProceedings of the National Academy of Sciences of the United States of America · 2026Article
- NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)PbioRxiv : the preprint server for biology · 2026Article
- Review
- Calcium homeostasis imbalance in sepsis: molecular mechanisms and therapeutic perspectives.Frontiers in medicine · 2026Review
- Organellar pH as an emerging vulnerability to exploit in cancer.Trends in cancer · 2026Review
- The ion channels of endomembranes.Physiological reviews · 2024Review
- Unexpected inhibition of the lipid kinase PIKfyve reveals an epistatic role for p38 MAPKs in endolysosomal fission and volume control.Cell death & disease · 2024Article
- Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Expanding the Toolbox: Novel Modulators of Endolysosomal Cation Channels.Handbook of experimental pharmacology · 2023Article
- NAADP-Dependent TPC Current.Handbook of experimental pharmacology · 2023Article
- NAADP-Mediated CaHandbook of experimental pharmacology · 2023Article
- Structure and Function of Plant and Mammalian TPC Channels.Handbook of experimental pharmacology · 2023Article
- Two-pore channels: going with the flows.Biochemical Society transactions · 2022Article
- Review
- Unexpected Motherhood-Triggered Hearing Loss in the Two-Pore Channel (TPC) Mutant Mouse.Biomedicines · 2022Article
- Parkinson's disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes.Cell · 2022Article
- Diversity of two-pore channels and the accessory NAADP receptors in intracellular CaCell calcium · 2022Review
- Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)PCell calcium · 2022Review
- Current Methods to Unravel the Functional Properties of Lysosomal Ion Channels and Transporters.Cells · 2022Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.