Nicotinic adenine acid dinucleotide phosphate (NAADP) is one of the most potent endogenous Ca(2+) mobilizing messengers. NAADP mobilizes Ca(2+) from an acidic lysosome-related store, which can be subsequently amplified into global Ca(2+) waves by calcium-induced calcium release (CICR) from ER/SR via Ins(1,4,5)P 3 receptors or ryanodine receptors. A body of evidence indicates that 2 pore channel 2 (TPC2), a new member of the superfamily of voltage-gated ion channels containing 12 putative transmembrane segments, is the long sought after NAADP receptor. Activation of NAADP/TPC2/Ca(2+) signaling inhibits the fusion between autophagosome and lysosome by alkalizing the lysosomal pH, thereby arresting autophagic flux. In addition, TPC2 is downregulated during neural differentiation of mouse embryonic stem (ES) cells, and TPC2 downregulation actually facilitates the neural lineage entry of ES cells. Here we propose the mechanism underlying how NAADP-induced Ca(2+) release increases lysosomal pH and discuss the role of TPC2 in neural differentiation of mouse ES cells.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984295 | PMC |
| http://dx.doi.org/10.4161/cib.27595 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Imaging Initial Ca2+ Microdomains in Primary T Cells.
J Vis Exp
October 2024
The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf;
Article Synopsis
- * When T cell receptors are activated, NAADP is quickly produced, interacting with specific proteins that trigger the release of calcium from internal stores, leading to a rise in intracellular calcium levels.
- * A new high-resolution imaging technique using two calcium indicators, along with a Python-based detection system, allows for the precise capture and analysis of these dynamic Ca microdomains in T cells and other cell types.
Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels.
Proc Natl Acad Sci U S A
August 2024
Department of Biochemistry, Structural Bioinformatics and Computational Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
Two-pore channels are pathophysiologically important Na- and Ca-permeable channels expressed in lysosomes and other acidic organelles. Unlike most other ion channels, their permeability is malleable and ligand-tuned such that when gated by the signaling lipid PI(3,5)P, they are more Na-selective than when gated by the Ca mobilizing messenger nicotinic acid adenine dinucleotide phosphate. However, the structural basis that underlies such plasticity and single-channel behavior more generally remains poorly understood.
View Article and Find Full Text PDFOCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage.
J Clin Invest
April 2024
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents.
View Article and Find Full Text PDFNeighbourhood Watch: Two-pore-2 channels talking to IP3 receptors.
Cell Calcium
May 2024
Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular & Integrative Biology, Crown Street, University of Liverpool, Liverpool L69 3BX, United Kingdom. Electronic address:
The recent elegant study by Y. Yuan and colleagues examined functional relationships between the lysosomal two-pore channels 2 (TPC2) and IP3 receptors (IP3Rs) located in the endoplasmic reticulum [1]. The findings of this study suggest functional coupling of these channels and receptors.
View Article and Find Full Text PDFTwo-pore channel-2 and inositol trisphosphate receptors coordinate Ca signals between lysosomes and the endoplasmic reticulum.
Cell Rep
January 2024
Department of Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT London, UK. Electronic address:
Lysosomes and the endoplasmic reticulum (ER) are Ca stores mobilized by the second messengers NAADP and IP, respectively. Here, we establish Ca signals between the two sources as fundamental building blocks that couple local release to global changes in Ca. Cell-wide Ca signals evoked by activation of endogenous NAADP-sensitive channels on lysosomes comprise both local and global components and exhibit a major dependence on ER Ca despite their lysosomal origin.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!