ArticleThe Journal of biological chemistry2010
TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 129 papers, 1 of them a synthesis that pooled it.
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Who cites it
129 citing papers in PubMed, 1 synthesis or guideline pooled it, 221 citations in OpenAlex.
- The protein interaction networks of mucolipins and two-pore channels.Biochimica et biophysica acta. Molecular cell research · 2019Pooled it
- NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)PbioRxiv : the preprint server for biology · 2026Article
- Review
- In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel.The Journal of general physiology · 2025Article
- Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.Bioelectricity · 2025Review
- Two-pore channel 2 is required for soluble adenylyl cyclase-dependent regulation of melanosomal pH and melanin synthesis.Pigment cell & melanoma research · 2024Article
- Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.Structure (London, England : 1993) · 2024Article
- Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Deregulation of New Cell Death Mechanisms in Leukemia.Cancers · 2024Review
- Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-Mediated Calcium Signaling Is Active in Memory CD4Molecules (Basel, Switzerland) · 2024Article
- Convergent activation of CaScience signaling · 2023Article
- Lysosomal calcium loading promotes spontaneous calcium release by potentiating ryanodine receptors.Biophysical journal · 2023Article
- Lysosomal CaPNAS nexus · 2023Article
- A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator.Cell calcium · 2023Article
- Review
- NAADP-Dependent TPC Current.Handbook of experimental pharmacology · 2023Article
- The Plant Vacuole as Heterologous System to Characterize the Functional Properties of TPC Channels.Handbook of experimental pharmacology · 2023Article
- Biomolecular Markers of Brain Aging.Advances in experimental medicine and biology · 2023Article
- Characterization of Endo-Lysosomal Cation Channels Using Calcium Imaging.Handbook of experimental pharmacology · 2023Article
- Electrophysiological Techniques on the Study of Endolysosomal Ion Channels.Handbook of experimental pharmacology · 2023Article
69 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca(2+) required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP-induced release of Ca(2+) from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca(2+) release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca(2+) that will enable it to act as a Ca(2+) release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca(2+)] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca(2+) release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca(2+) release. Ned-19 antagonizes NAADP-activation of TPC2 in a non-competitive manner at 1 μM but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events.
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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.