| 2009 |
TPCN2 encodes a lysosomal protein forming homomers that mediates NAADP-dependent Ca2+ release from lysosomal stores; activated by low-nanomolar NAADP, desensitized by micromolar NAADP, insensitive to NADP, and Ca2+ release is abolished by pharmacological blockade of lysosomal Ca2+ storage but unaffected by ER Ca2+ store depletion. |
Overexpression in cells, lysosomal Ca2+ imaging, pharmacological manipulation (NAADP, NADP, lysosomal Ca2+ blockers, ER Ca2+ store depletion) |
Pflugers Archiv : European journal of physiology |
High |
19557428
|
| 2010 |
TPC2 is a cation channel with selectivity for Ca2+ that opens in response to NAADP in a concentration-dependent manner, with high-affinity activation and low-affinity inhibition sites; channel sensitivity to NAADP is steeply dependent on luminal [Ca2+], and luminal pH controls NAADP affinity, switching between reversible activation at low pH and irreversible activation at neutral pH. The selective NAADP blocker Ned-19 antagonizes TPC2 non-competitively. |
Single-channel patch-clamp electrophysiology of TPC2-expressing lipid bilayers/vesicles, pharmacological characterization with NAADP and Ned-19 |
The Journal of biological chemistry |
High |
20720007
|
| 2010 |
TPC2 mediates NAADP-dependent Ca2+ release from acidic lysosome-related organelles leading to smooth muscle contraction; contractile responses to NAADP were completely abolished and agonist-evoked (muscarinic) contractions were reduced and rendered independent of acidic Ca2+ stores in Tpcn2−/− mouse detrusor smooth muscle. |
Permeabilized smooth muscle contractility assays, Tpcn2−/− knockout mouse model, pharmacological Ca2+ store depletion |
The Journal of biological chemistry |
High |
20547763
|
| 2012 |
Endogenously expressed TPC2 associates with STIM1 and Orai1 (but not TRPC1) upon intracellular Ca2+ store depletion (not in resting cells), and silencing TPC2 attenuates store-operated Ca2+ entry (SOCE) evoked by thapsigargin or thrombin without affecting resting store capacity. |
siRNA knockdown, co-immunoprecipitation, Ca2+ entry measurements (fluorescence), surface biotinylation |
Biochimica et biophysica acta |
Medium |
23077736
|
| 2013 |
TPC2 overexpression inhibits autophagosomal-lysosomal fusion by alkalinizing lysosomal pH, causing autophagosome accumulation; NAADP-AM treatment exacerbates this effect, TPC2 knockdown or Ned-19 treatment reduces it, and lysosomal re-acidification rescues the block. TPC2 overexpression also prevents Rab-7 recruitment to autophagosomes. |
TPC2 overexpression and siRNA knockdown, autophagosome/lysosome fusion assays, lysosomal pH measurement, NAADP-AM treatment, Ned-19 treatment, ATG5 knockdown epistasis, Rab-7 localization |
The Journal of biological chemistry |
High |
23836916
|
| 2014 |
Loss of Tpcn2 expression (but not Tpcn1) slows kinetics of ligand-induced PDGFRβ degradation dependent on lysosomal trafficking, while Tpcn1 loss impairs cholera toxin trafficking from plasma membrane to Golgi; neither knockout significantly affects resting endo-lysosomal pH or morphology. |
Tpcn2−/− and Tpcn1−/− mouse embryonic fibroblasts (MEFs), PDGFRβ degradation assay, cholera toxin trafficking assay, lysosomal pH measurement |
Molecular and cellular biology |
Medium |
25135478
|
| 2014 |
TPC2 in skeletal muscle contributes to lysosomal pH homeostasis, lysosomal protease activity, and autophagy signaling; Tpcn2−/− muscles show enhanced autophagy flux under starvation/colchicine stress with autophagosome accumulation, aberrant lysosomal pH, and reduced lysosomal protease activity. Association between mTOR and TPC2 was detected in skeletal muscle. |
Tpcn2−/− mouse model, autophagy flux assays (autophagosome accumulation with colchicine), lysosomal pH and protease activity measurements, co-immunoprecipitation of mTOR and TPC2 |
The Journal of biological chemistry |
Medium |
25480788
|
| 2014 |
Lysosomal enlargement and aggregation in LRRK2-G2019S Parkinson's disease patient fibroblasts are corrected by molecular silencing of TPC2 or pharmacological inhibition of TPC2 regulators (Rab7, NAADP, PtdIns(3,5)P2), and by buffering local Ca2+ increases; NAADP-evoked Ca2+ signals are exaggerated in diseased cells, placing TPC2 downstream of pathogenic LRRK2. |
TPC2 siRNA knockdown, pharmacological inhibition, Ca2+ imaging in patient-derived fibroblasts, lysosomal morphology analysis |
Journal of cell science |
Medium |
25416817
|
| 2016 |
TPC2 localizes to the melanosome-limiting membrane (confirmed by confocal, immunogold EM, and immunomagnetic isolation) and regulates melanosome pH and size; TPC2 knockout increases melanin content and melanosome size and causes melanosome lumen to be less acidic; these effects are rescued by TPC2-GFP re-expression. TPC2-mediated Ca2+ release from melanosomes is decreased in KO cells. |
CRISPR/Cas9 knockout, siRNA knockdown, confocal fluorescence microscopy, immunogold EM, immunomagnetic organelle isolation, genetically encoded pH sensor (melanosome-targeted), Ca2+ sensor (tyrosinase-GCaMP6), melanin quantification |
Proceedings of the National Academy of Sciences of the United States of America |
High |
27140606
|
| 2017 |
Two human TPC2 polymorphisms associated with blond hair (M484L/rs35264875 and G734E/rs3829241) both produce gain-of-function channel activity by independent mechanisms, as directly measured by endolysosomal patch-clamp electrophysiology in isolated endolysosomal organelles from variant-carrier fibroblasts. |
Endolysosomal patch-clamp electrophysiology, genotype/phenotype analysis in >100 individuals, fibroblasts from WT and polymorphic variant carriers |
Proceedings of the National Academy of Sciences of the United States of America |
High |
28923947
|
| 2017 |
TPC2-mediated Ca2+ release from acidic stores is required for slow muscle cell myofibrillogenesis and myotomal patterning in zebrafish; TPC2 knockdown (two non-overlapping MOs), knockout (CRISPR), or pharmacological inhibition disrupts these processes, which are rescued by tpcn2-mRNA injection or IP3R/RyR agonists. STED microscopy revealed close proximity (~52–87 nm) between RyR clusters in SR terminal cisternae and TPC2 in lysosomes. |
Morpholino knockdown, CRISPR knockout, pharmacological inhibition (bafilomycin A1, trans-ned-19), mRNA rescue, IP3R/RyR agonist rescue, STED super-resolution microscopy |
Developmental biology |
High |
28390800
|
| 2017 |
Under low-Mg2+ conditions, PI(3,5)P2 activates TPC2 to increase intracellular Na+, depolarize membrane potential, and thereby inhibit osteoclast differentiation; under normal Mg2+ conditions TPC2 promotes osteoclastogenesis. |
TPC2 functional studies in osteoclast differentiation assays, PI(3,5)P2 signaling pathway perturbation, light-sensitive membrane depolarization system, myo-inositol supplementation in vivo |
The Journal of biological chemistry |
Medium |
29084844
|
| 2018 |
TPC2-dependent Ca2+ release from acidic intracellular stores mediates adrenaline-stimulated glucagon secretion in pancreatic α-cells; genetic or pharmacological inhibition of Tpc2 abolishes adrenaline's stimulatory effect on glucagon secretion and reduces Ca2+ elevation; downstream amplification occurs via Ca2+-induced Ca2+ release from the SR/ER (ryanodine-sensitive), placing TPC2 upstream of RyR in a cAMP/PKA/EPAC2-dependent hierarchy. |
Tpc2 genetic knockout, pharmacological inhibition, electrophysiology, Ca2+ imaging, PKA activity imaging, glucagon secretion measurements in mouse and human islets |
Diabetes |
High |
29563152
|
| 2018 |
TPC2 overexpression inhibits autophagosome-lysosome fusion (increasing lysosomal pH and autophagosome accumulation) and decreases extracellular vesicle secretion, while TPC2 knockdown increases EV secretion and inhibits cancer cell migration. |
TPC2 overexpression, siRNA knockdown, autophagy flux assays, extracellular vesicle quantification, TFEB nuclear translocation, migration assay |
Experimental cell research |
Medium |
29990474
|
| 2020 |
TPC2 ion selectivity depends on the activating ligand: NAADP activates non-selective cation currents and robust Ca2+ signals, while PI(3,5)P2 activates Na+-selective currents and weaker Ca2+ signals; mutation of a single TPC2 residue differentially abolishes each agonist's action; NAADP and PI(3,5)P2 drive opposing changes in lysosomal pH and exocytosis. |
High-throughput agonist screen, endolysosomal patch-clamp electrophysiology, site-directed mutagenesis, lysosomal pH measurement, lysosomal exocytosis assay |
eLife |
High |
32167471
|
| 2020 |
TPC2 loss in metastatic melanoma cells increases invasiveness and is associated with reduced ORAI1/SOCE and reduced PKC-βII, leading to activation of YAP/TAZ target genes; this identifies ORAI1/Ca2+/PKC-βII as a mechanistic link between TPC2 loss and YAP/TAZ-driven metastatic behavior. |
CRISPR/Cas9 TPC2 knockout, invasion assay, western blot, siRNA knockdown of ORAI1 and PKC-βII, transcriptome analysis |
Cancers |
Medium |
32846966
|
| 2020 |
TPC2 knockdown attenuates Ca2+ signaling and inhibits axon extension of caudal primary motor neurons (CaPs) in zebrafish; these effects are replicated by CRISPR knockout and pharmacological inhibition; ARC1-like knockdown also attenuates CaP Ca2+ transients and axon extension, suggesting a link between ARC1-like and TPC2 in Ca2+ signaling during axon extension. |
Morpholino knockdown, CRISPR knockout, pharmacological inhibition, Ca2+ imaging in CaP growth cones, morpholino knockdown of ARC1-like |
Journal of cell science |
Medium |
32546534
|
| 2021 |
The common human TPC2 variant L564P is a prerequisite for the blond hair-associated M484L gain-of-function effect; without L564P background, M484L does not produce gain-of-function; characterized by endolysosomal patch-clamp electrophysiology. |
Endolysosomal patch-clamp electrophysiology of polymorphic TPC2 variants, genome variation analysis |
PLoS genetics |
Medium |
33465068
|
| 2021 |
TPC2 knockout reduces cancer cell proliferation and energy metabolism in vitro and abrogates tumor growth in vivo; tetrandrine analogs developed as TPC2 inhibitors impair proangiogenic signaling of endothelial cells. |
CRISPR/Cas9 knockout, in vitro proliferation assays, metabolic assays, in vivo tumor xenograft models, pharmacological inhibition with synthesized tetrandrine analogs |
Cell chemical biology |
Medium |
33626324
|
| 2021 |
TPC2 inhibition (genetic or pharmacological) reduces MITF protein levels via increased GSK3β-mediated MITF degradation, reduces melanoma proliferation/migration/invasion, and increases tyrosinase activity and melanin production; these are mediated through TPC2 activity in both endolysosomes and melanosomes. |
CRISPR/Cas9 and siRNA knockdown, pharmacological inhibition (flavonoids), western blot for MITF/GSK3β, tyrosinase activity assay, melanin quantification, migration/invasion assay |
Scientific reports |
Medium |
33875769
|
| 2022 |
TPC2 co-activation by NAADP and PI(3,5)P2 increases Ca2+ permeability independently of changes in ion selectivity (acting as a coincidence detector); NAADP renders TPC2 Ca2+-permeable and PI(3,5)P2 renders it Na+-selective, but co-activation synergistically increases Ca2+ flux; this controls lysosomal pH and motility. |
Endolysosomal patch-clamp electrophysiology, cell-permeable NAADP and PI(3,5)P2 mimetics in live cells, lysosomal pH and motility measurements |
Nature communications |
High |
35918320
|
| 2022 |
Small molecule activation of TPC2 (Ca2+-permeable endolysosomal channel) promotes lysosomal exocytosis and autophagy, rescuing cellular phenotypes (cholesterol/lipofuscin accumulation, abnormal vacuoles) in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease patient fibroblasts and in iPSC-derived neurons, and reduces pathology in the MLIV mouse model in vivo. |
Pharmacological TPC2 activation (TPC2-A1-P), CRISPR-generated isogenic iPSC models, patient fibroblasts, electron microscopy, cholesterol/lipofuscin assays, in vivo MLIV mouse model |
EMBO molecular medicine |
High |
35929194
|
| 2022 |
TPC2 loss in drug-resistant leukemia cells sensitizes them to chemotherapy via two mechanisms: (1) increased lysosomal pH impairs lysosomal drug sequestration, increasing nuclear doxorubicin accumulation and DNA damage; (2) morphological lysosomal changes and protein dysregulation increase lysosomal membrane permeability, releasing cathepsin B and triggering Bid truncation and lysosomal cell death. |
CRISPR/Cas9 TPC2 knockout, pharmacological inhibition (naringenin, tetrandrine), drug accumulation assay, DNA damage assay, lysosomal stability assay, cathepsin B cytosolic localization, Bid western blot, cathepsin B inhibitor rescue, patient-derived xenograft cells |
Cell death & disease |
High |
35915060
|
| 2023 |
TPC2 generates local Ca2+ nanodomains (~42 µM) around the channel mouth during phagocytosis (measured by GECI fused directly to TPC2), and TPC2 and TRPML1 on the same lysosomes generate autonomous, largely insulated Ca2+ nanodomains; TPC2 nanodomains couple specifically to dynamin activation during Fc-receptor-mediated phagocytosis. |
Genetically encoded Ca2+ indicators (GECIs) fused to TPC2, Ca2+ nanodomain optical recording, signal calibration for channel-GECI distance, macrophage phagocytosis assay |
Cell calcium |
High |
37742482
|
| 2023 |
A de novo gain-of-function TPC2 mutation R210C causes constitutive channel activation and markedly increased affinity to PI(3,5)P2, producing enhanced lysosomal Ca2+ release, hyper-acidification of endolysosomes, and albinism in a dominant inheritance pattern; homologous R194C knock-in mice exhibit hypopigmentation and enlarged endolysosomes. |
Inside-out plasma membrane patch-clamp of targeted TPC2 R210C, direct recording of enlarged endolysosomal vacuoles, CRISPR knock-in mice (R194C), lysosomal pH measurement, electron microscopy |
Nature communications |
High |
36641477
|
| 2023 |
Pharmacological inhibition of TPC2 (Ned-19) during hypoxia in cortical neurons prevents ER stress (reduces GRP78 and caspase 9), restores organellar Ca2+ homeostasis, blocks autophagic flux, and confers neuroprotection; in rats subjected to tMCAO, Ned-19 reduces infarct volume and neurological deficits. Ned-19's effect is reversed by NAADP-AM. |
TPC2 siRNA knockdown, Ned-19 pharmacological inhibition, NAADP-AM rescue, OGD/R in primary cortical neurons, rat tMCAO model, western blot, Ca2+ imaging |
Neurobiology of disease |
Medium |
36708960
|
| 2023 |
TPC2 pharmacological inhibition (naringenin, tetrandrine, SG-094) inhibits osteoblast differentiation from hMSCs and bone mineralization; mechanistically, TPC2 inhibition reduces beclin-1 and LC3-II and increases phosphorylated mTOR, and rapamycin (mTOR inhibitor) reverses TPC2 inhibitor-induced osteoblast differentiation, placing TPC2 upstream of mTOR in autophagy regulation during osteoblastogenesis. |
Primary hMSC differentiation assay, Saos-2 mineralization assay, pharmacological TPC2 inhibitors, western blot (beclin-1, LC3-II, p-mTOR), rapamycin epistasis |
Journal of endocrinological investigation |
Medium |
42090110
|
| 2025 |
The common LRRK2 G2019S mutation selectively exaggerates depolarization-induced Ca2+ entry in dopaminergic neurons; TPC2 chemical or molecular inhibition reverses this excess Ca2+ entry. In Drosophila (which lack endogenous TPCs), expression of human TPC2 phenocopies LRRK2 G2019S dopaminergic dysfunction; this dysfunction requires an intact pore, correct subcellular targeting, and Rab interactivity of TPC2. A biased TPC2 agonist that reduces Ca2+ permeability also corrected deviant Ca2+ entry. |
Ca2+ imaging in dopaminergic neurons, molecular and pharmacological TPC2 inhibition, Drosophila in vivo model with human TPC2 expression, TPC2 mutant analysis (pore, targeting, Rab-interactivity), biased TPC2 agonist |
The Journal of cell biology |
High |
40279672
|
| 2025 |
OCA2 (a Cl- channel) modulates TPC2 activity via melanosomal pH; cytosolic high Cl- inhibits and luminal high Cl- enhances TPC2 channel activity; OCA2 loss-of-function combined with TPCN2 gain-of-function (A24V) acts synergistically to cause hypopigmentation in mice and patients, confirmed by CRISPR/Cas9 KO and knock-in mouse models. |
Patch-clamp analysis of TPC2 A24V, CRISPR/Cas9 knockout and knock-in mouse models, Cl- concentration manipulation in patch-clamp, melanin/melanosomal pH measurements |
The Journal of investigative dermatology |
High |
41443368
|
| 2025 |
TPC2-mediated Ca2+ release from lysosomes promotes Rab46-dependent detachment of Ang2-positive Weibel-Palade bodies (WPBs) from the microtubule organising centre (MTOC) in endothelial cells, enabling angiopoietin-2 secretion; TPC inhibitors increase WPB clustering at MTOC and reduce Ang2 secretion, while a TPC2 agonist has opposite effects. |
Ca2+ imaging, high-resolution light microscopy, pharmacological TPC inhibition (Ned19, tetrandrine) and TPC2 agonist (TPC2-A1-N), Ang2 secretion measurement |
bioRxivpreprint |
Medium |
|
| 2025 |
Chlorpromazine and clomipramine activate TPC2 lysosomal channel (producing large inwardly-rectifying currents blocked by trans-Ned-19 and siTPC2), inducing TFEB nuclear translocation and autophagy activation (via ULK, AMPK-α); TPC2 activation by these drugs protects motor neurons from L-BMAA-induced neurodegeneration and is partially dependent on TPC2 (siTPC2 reversal). |
Patch-clamp electrophysiology on enlarged lysosomes, TFEB nuclear translocation assay, western blot (ULK, AMPK-α, LC3-II/p62), siTPC2 knockdown, LDH/cytochrome C release, cell viability assay |
Biochemical pharmacology |
Medium |
40796055
|
| 2025 |
Under glucose deprivation-restoration, mTOR inactivation leads to lysosomal iron release via TPC2 and ferritin degradation through ferritinophagy, elevating intracellular iron and promoting ferroptosis in renal tubular cells; TPC2 is mechanistically downstream of the V-ATPase-mTOR axis for lysosomal iron release. |
In vitro OGSD-R and in vivo IR models, immunofluorescence, immunoblotting, biochemical iron assays, pathway perturbation (mTOR inhibition/activation, TPC2 manipulation) |
Free radical biology & medicine |
Medium |
40379157
|
| 2026 |
TPC2 activation amplifies lysosome-to-mitochondria Ca2+ transfer via an ER-dependent relay requiring IP3 receptors and the mitochondrial calcium uniporter; moderate TPC2 activation transiently enhances oxidative phosphorylation, while sustained activation increases susceptibility to mitochondrial permeability transition. In stroke models, TPC2 hyperactivation exacerbates injury and acute pharmacological inhibition at reperfusion is neuroprotective. |
TPC2 pharmacological activation/inhibition, organelle-targeted Ca2+ imaging, IP3R and MCU knockdown epistasis, mitochondrial membrane potential assay, seahorse metabolic assay, stroke models, human iPSC-derived neurons |
bioRxivpreprint |
Medium |
41867847
|
| 2026 |
NAADP-dependent TPC2 activity is required for efficient ferroptosis induction in HCC cells; TPC2 loss renders HCC cells resistant to ferroptosis (by system Xc- inhibition or GPX4 blockade), associated with reduced lipid peroxidation, altered Ca2+ signaling, and depletion of polyunsaturated phosphatidylethanolamine species linked to decreased ACSL4 expression. |
Pharmacological TPC2 modulation, genetic knockout, flow cytometry-based cell death and lipid peroxidation assays, lipidomics, Ca2+ measurement |
Antioxidants (Basel, Switzerland) |
Medium |
42193240
|