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Showing TPCN2 — TPC2 is a alias.

TPCN2

Two pore channel protein 2 · UniProt Q8NHX9

Length
752 aa
Mass
85.2 kDa
Annotated
2026-06-10
51 papers in source corpus 33 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TPCN2 (TPC2) is a homomeric cation channel of lysosomal, endolysosomal, and melanosomal membranes that gates Ca2+ release from acidic intracellular stores to control organelle homeostasis, autophagy, exocytosis, and pigmentation (PMID:19557428, PMID:27140606, PMID:32167471). Single-channel and endolysosomal patch-clamp recordings establish it as a Ca2+-permeable channel activated by low-nanomolar NAADP, with luminal Ca2+ and pH steeply tuning its sensitivity and switching activation between reversible and irreversible modes (PMID:19557428, PMID:20720007). Ligand identity dictates ion selectivity: NAADP drives non-selective, robustly Ca2+-permeable currents whereas PI(3,5)P2 drives Na+-selective currents, and co-activation by both acts as a coincidence detector that synergistically maximizes Ca2+ flux through a single critical pore residue (PMID:32167471, PMID:35918320). By regulating these fluxes TPC2 sets lysosomal pH, protease activity, and exocytosis, controlling autophagosome-lysosome fusion such that overexpression alkalinizes lysosomes and blocks fusion while genetic loss perturbs lysosomal pH and cargo trafficking (PMID:23836916, PMID:25480788, PMID:25135478). In melanosomes it controls luminal pH, melanosome size, and melanin content, and its activity is modulated by the chloride channel OCA2 (PMID:27140606, PMID:41443368). Human gain-of-function variants (M484L/G734E, the L564P-dependent epistasis, and the de novo R210C and A24V mutations) produce hyperactive channels causing blond hair and dominant albinism, while loss-of-function increases pigmentation in part through GSK3β-mediated MITF stabilization (PMID:28923947, PMID:33465068, PMID:36641477, PMID:41443368, PMID:33875769). TPC2-generated local Ca2+ nanodomains (~42 µM at the channel mouth) are decoded by specific effectors including dynamin during phagocytosis, Rab46 during Weibel-Palade body trafficking, and the SR/ER RyR for Ca2+-induced Ca2+ release driving smooth muscle contraction and adrenaline-stimulated glucagon secretion (PMID:37742482, PMID:20547763, PMID:29563152). Through an mTOR-coupled, lysosome-ER-mitochondria Ca2+ relay TPC2 further links autophagy, iron release, lipid peroxidation, and mitochondrial energetics, making it a driver of ferroptosis and a target in lysosomal storage disease, melanoma, leukemia, and LRRK2-G2019S Parkinson's disease (PMID:25480788, PMID:40379157, PMID:42193240, PMID:35929194, PMID:35915060, PMID:40279672).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2009 High

    Established the founding molecular identity of TPC2 as a lysosomal channel coupling the second messenger NAADP to Ca2+ release from acidic stores, distinct from ER stores.

    Evidence Overexpression with lysosomal Ca2+ imaging and pharmacology (NAADP, NADP, lysosomal vs ER store depletion)

    PMID:19557428

    Open questions at the time
    • Direct biophysical conductance not yet measured
    • Endogenous channel behavior not addressed
  2. 2010 High

    Defined the biophysics and gating logic of the channel, showing NAADP gates a Ca2+-permeable conductance with dual activation/inhibition sites tuned by luminal Ca2+ and pH.

    Evidence Single-channel patch-clamp of TPC2 in bilayers/vesicles with Ned-19 pharmacology

    PMID:20720007

    Open questions at the time
    • Did not address Na+ permeability or alternative ligands
    • Pore residues governing selectivity unmapped
  3. 2010 High

    Provided in vivo proof that TPC2-dependent acidic-store Ca2+ release drives a physiological output (smooth muscle contraction) via a genetic knockout.

    Evidence Tpcn2−/− mouse detrusor permeabilized contractility with NAADP and store depletion

    PMID:20547763

    Open questions at the time
    • Downstream Ca2+ amplification machinery not yet defined
    • Channel-effector coupling distance unknown
  4. 2012 Medium

    Connected TPC2 to store-operated Ca2+ entry by showing depletion-dependent association with STIM1/Orai1, hinting at crosstalk between acidic and ER store signaling.

    Evidence siRNA, co-IP, surface biotinylation, and SOCE measurements in two cell lines

    PMID:23077736

    Open questions at the time
    • Single lab, no reciprocal validation of complex
    • Mechanism of depletion-induced association unresolved
  5. 2013 High

    Showed TPC2 governs autophagosome-lysosome fusion through lysosomal pH, establishing a regulatory role in the late autophagy pathway.

    Evidence Gain/loss-of-function, pH measurement, ATG5 epistasis, Rab7 localization, lysosomal re-acidification rescue

    PMID:23836916

    Open questions at the time
    • Whether effect requires Ca2+ vs cation flux per se unclear
    • Largely overexpression-driven
  6. 2014 Medium

    Clarified TPC2 roles in lysosomal cargo trafficking, protease activity, and autophagy flux, and detected an mTOR association, placing TPC2 within nutrient/autophagy signaling.

    Evidence Tpcn2−/− MEFs and muscle (PDGFRβ degradation, cholera toxin trafficking, autophagy flux, pH/protease assays, mTOR co-IP)

    PMID:25135478 PMID:25480788

    Open questions at the time
    • mTOR interaction not reciprocally validated
    • Direct vs indirect coupling to mTOR unresolved
  7. 2014 Medium

    Placed TPC2 downstream of pathogenic LRRK2-G2019S, linking exaggerated NAADP/TPC2 Ca2+ signaling to lysosomal dysmorphology in Parkinson's disease cells.

    Evidence TPC2 silencing/pharmacology and Ca2+ imaging in patient-derived fibroblasts

    PMID:25416817

    Open questions at the time
    • Mechanism connecting LRRK2 to TPC2 hyperactivity not defined
    • Single lab, fibroblast model only
  8. 2016 High

    Localized TPC2 to the melanosome membrane and established its control of melanosome pH, size, and melanin content, founding the pigmentation mechanism.

    Evidence CRISPR KO/rescue, immunogold EM, organelle isolation, organelle-targeted pH and Ca2+ sensors, melanin quantification

    PMID:27140606

    Open questions at the time
    • Downstream pigmentation effectors not yet identified
    • Relationship to channel ligands in melanosomes unclear
  9. 2017 High

    Linked human channel-activity variants to a heritable trait, showing two blond-hair polymorphisms confer gain-of-function by independent mechanisms.

    Evidence Endolysosomal patch-clamp of variant-carrier fibroblasts plus cohort genotyping

    PMID:28923947

    Open questions at the time
    • Structural basis of each gain-of-function distinct mechanism unresolved
    • Variant interactions not yet tested
  10. 2017 High

    Extended TPC2 Ca2+ signaling to developmental and differentiation contexts and revealed nanoscale proximity to RyR clusters supporting Ca2+-induced Ca2+ release.

    Evidence Zebrafish MO/CRISPR/pharmacology with mRNA and RyR/IP3R agonist rescue and STED microscopy; osteoclast differentiation assays with PI(3,5)P2

    PMID:28390800 PMID:29084844

    Open questions at the time
    • Physical TPC2-RyR coupling mechanism not biochemically defined
    • Context-dependent (Mg2+) bidirectional effects mechanistically unclear
  11. 2018 High

    Defined a signaling hierarchy in which TPC2 lies upstream of RyR-mediated CICR during adrenaline-stimulated glucagon secretion, and linked TPC2 to extracellular vesicle secretion and migration.

    Evidence Tpc2 KO/pharmacology, electrophysiology, Ca2+/PKA imaging, glucagon assays in mouse and human islets; EV and migration assays with TFEB readout

    PMID:29563152 PMID:29990474

    Open questions at the time
    • Spatial coupling of TPC2 to SR RyR not directly imaged here
    • EV/migration mechanism (single lab) less defined
  12. 2020 High

    Resolved the central gating principle that activating ligand dictates ion selectivity through a single pore residue, distinguishing NAADP-driven Ca2+ from PI(3,5)P2-driven Na+ currents.

    Evidence High-throughput agonist screen, endolysosomal patch-clamp, site-directed mutagenesis, pH and exocytosis assays

    PMID:32167471

    Open questions at the time
    • Structural conformations underlying selectivity switch not solved
    • How a single residue toggles selectivity unresolved
  13. 2020 Medium

    Demonstrated tumor-suppressive consequences of TPC2 loss in melanoma via ORAI1/Ca2+/PKC-βII and YAP/TAZ, and tied TPC2 to motor neuron axon Ca2+ signaling.

    Evidence CRISPR KO, invasion assay, RNAi epistasis, transcriptomics; zebrafish MO/CRISPR/pharmacology with Ca2+ imaging

    PMID:32546534 PMID:32846966

    Open questions at the time
    • Direct link from lysosomal TPC2 to plasma-membrane ORAI1 signaling unclear
    • ARC1-like–TPC2 relationship correlative
  14. 2021 Medium

    Established variant epistasis and further pigmentation mechanism, showing L564P is a prerequisite for M484L gain-of-function and that TPC2 controls MITF via GSK3β.

    Evidence Endolysosomal patch-clamp of polymorphic variants; CRISPR/siRNA/pharmacology with MITF/GSK3β blots and tyrosinase/melanin assays

    PMID:33465068 PMID:33875769

    Open questions at the time
    • Biophysical basis of L564P permissiveness undefined
    • Link from channel activity to GSK3β not mechanistically traced
  15. 2021 Medium

    Validated TPC2 as a cancer-relevant target by showing knockout impairs proliferation, metabolism, and tumor growth, with tetrandrine-analog inhibitors developed.

    Evidence CRISPR KO, proliferation/metabolic assays, xenografts, synthesized pharmacological inhibitors

    PMID:33626324

    Open questions at the time
    • Metabolic mechanism of TPC2 dependence not fully resolved
    • Inhibitor selectivity in vivo not exhaustively characterized
  16. 2022 High

    Defined the coincidence-detector mechanism wherein NAADP and PI(3,5)P2 co-activation synergistically boosts Ca2+ flux independent of selectivity, controlling lysosomal pH and motility.

    Evidence Endolysosomal patch-clamp with cell-permeable ligand mimetics and live-cell pH/motility assays

    PMID:35918320

    Open questions at the time
    • Structural basis of synergistic gating unresolved
    • Physiological contexts of dual ligand co-activation untested
  17. 2022 High

    Demonstrated therapeutic leverage of TPC2 activity in disease: small-molecule activation rescues lysosomal storage disease pathology, while loss sensitizes drug-resistant leukemia to chemotherapy.

    Evidence Pharmacological TPC2-A1-P in iPSC/patient fibroblasts and MLIV mice; CRISPR KO and inhibitors with drug accumulation, DNA damage, and lysosomal death readouts in leukemia

    PMID:35915060 PMID:35929194

    Open questions at the time
    • How activation simultaneously promotes exocytosis and corrects multiple LSDs mechanistically unresolved
    • Generalizability across tumor types untested
  18. 2023 High

    Quantified channel-proximal Ca2+ nanodomains and established effector-specific decoding, showing ~42 µM local Ca2+ couples TPC2 to dynamin during phagocytosis with autonomy from co-resident TRPML1.

    Evidence GECI fused to TPC2 with calibrated nanodomain optical recording in macrophage phagocytosis

    PMID:37742482

    Open questions at the time
    • How insulation between TPC2 and TRPML1 domains is maintained unknown
    • Physical basis of dynamin recruitment not defined
  19. 2023 High

    Identified a de novo gain-of-function mutation (R210C) causing dominant albinism through constitutive activation and increased PI(3,5)P2 affinity, with a knock-in mouse phenocopy.

    Evidence Inside-out and enlarged-vacuole patch-clamp, R194C knock-in mice, pH and EM phenotyping

    PMID:36641477

    Open questions at the time
    • Structural mechanism of constitutive opening unresolved
    • Why hyperactivation reduces pigmentation despite hyper-acidification unclear
  20. 2023 Medium

    Extended TPC2's pathological role to ischemia, showing inhibition reduces ER stress and autophagic flux and is neuroprotective in stroke.

    Evidence siRNA, Ned-19 with NAADP-AM rescue, OGD/R neurons, rat tMCAO, blots and Ca2+ imaging

    PMID:36708960

    Open questions at the time
    • Causal chain from TPC2 to ER stress not fully dissected
    • Single lab
  21. 2025 High

    Established structure-function requirements for TPC2 in LRRK2-G2019S dopaminergic dysfunction, showing pore integrity, targeting, and Rab interactivity are all required and a biased agonist corrects pathology.

    Evidence Ca2+ imaging in dopaminergic neurons, Drosophila human-TPC2 reconstitution, structure-function mutants, biased agonist

    PMID:40279672

    Open questions at the time
    • Identity of the relevant Rab interactor not defined here
    • How LRRK2 amplifies TPC2 Ca2+ entry mechanistically open
  22. 2025 High

    Identified physiological regulators and effectors of TPC2: OCA2-derived chloride modulates channel activity (digenic albinism), and TPC2 Ca2+ drives Rab46-dependent Weibel-Palade body trafficking for Ang2 secretion.

    Evidence Patch-clamp with Cl- manipulation, CRISPR KO/knock-in mice; Ca2+ imaging and pharmacology with Ang2 secretion readout (preprint for WPB study)

    PMID:41443368

    Open questions at the time
    • Direct OCA2-TPC2 physical interaction not established
    • Rab46 recruitment mechanism by Ca2+ nanodomains undefined
  23. 2025 Medium

    Linked TPC2 to drug-induced TFEB/autophagy activation and to lysosomal iron release driving ferroptosis, placing TPC2 downstream of V-ATPase-mTOR.

    Evidence Patch-clamp with chlorpromazine/clomipramine, TFEB/ULK/AMPK readouts and siTPC2 in neurons; OGSD-R and IR models with iron assays and mTOR perturbation

    PMID:40379157 PMID:40796055

    Open questions at the time
    • Whether iron permeates TPC2 directly or via secondary release unresolved
    • Single-lab mechanistic dissection
  24. 2026 Medium

    Defined a lysosome-ER-mitochondria Ca2+ relay through which TPC2 tunes mitochondrial energetics and ferroptosis sensitivity.

    Evidence Pharmacological TPC2 modulation, organelle-targeted Ca2+ imaging, IP3R/MCU epistasis, metabolic and stroke assays, iPSC neurons (preprint); NAADP-TPC2 dependence of HCC ferroptosis with lipidomics

    PMID:41867847 PMID:42193240

    Open questions at the time
    • Physical lysosome-ER-mitochondria contact architecture undefined
    • ACSL4/PUFA-PE regulation downstream of TPC2 Ca2+ not mechanistically traced
    • One study is a preprint

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single pore residue toggles ligand-dependent selectivity, how distinct effectors (dynamin, Rab46, RyR, mTOR) are physically recruited to channel-proximal Ca2+ nanodomains, and the structural basis of gain-of-function disease variants remain unresolved.
  • No high-resolution structure linking gating, selectivity, and ligand sites in the timeline
  • Physical recruitment mechanism for each downstream effector undefined
  • Architecture of inter-organelle Ca2+ relay contacts uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0008289 lipid binding 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005764 lysosome 6 GO:0005768 endosome 3
Pathway
R-HSA-9612973 Autophagy 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
DNMMTOROCA2ORAI1RAB46RAB7RYRSTIM1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
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

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The two-pore channel TPCN2 mediates NAADP-dependent Ca(2+)-release from lysosomal stores. Pflugers Archiv : European journal of physiology 250 19557428
2010 TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. The Journal of biological chemistry 195 20720007
2014 Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. Journal of cell science 169 25416817
2020 Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function. eLife 142 32167471
2016 TPC2 controls pigmentation by regulating melanosome pH and size. Proceedings of the National Academy of Sciences of the United States of America 118 27140606
2013 Two pore channel 2 (TPC2) inhibits autophagosomal-lysosomal fusion by alkalinizing lysosomal pH. The Journal of biological chemistry 85 23836916
2018 Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells. Diabetes 83 29563152
2014 TPC1 has two variant isoforms, and their removal has different effects on endo-lysosomal functions compared to loss of TPC2. Molecular and cellular biology 79 25135478
2014 Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. The Journal of biological chemistry 74 25480788
2017 TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms. Proceedings of the National Academy of Sciences of the United States of America 71 28923947
2010 TPC2 proteins mediate nicotinic acid adenine dinucleotide phosphate (NAADP)- and agonist-evoked contractions of smooth muscle. The Journal of biological chemistry 71 20547763
2021 Gene editing and synthetically accessible inhibitors reveal role for TPC2 in HCC cell proliferation and tumor growth. Cell chemical biology 52 33626324
2021 Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2. Scientific reports 48 33875769
2022 TPC2 rescues lysosomal storage in mucolipidosis type IV, Niemann-Pick type C1, and Batten disease. EMBO molecular medicine 46 35929194
2018 TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells. Experimental cell research 43 29990474
2020 Pharmacological hypothesis: TPC2 antagonist tetrandrine as a potential therapeutic agent for COVID-19. Pharmacology research & perspectives 40 32930523
2023 A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation. Nature communications 31 36641477
2021 Human genome diversity data reveal that L564P is the predominant TPC2 variant and a prerequisite for the blond hair associated M484L gain-of-function effect. PLoS genetics 30 33465068
2022 Segregated cation flux by TPC2 biases Ca2+ signaling through lysosomes. Nature communications 29 35918320
2015 The two pore channel TPC2 is dispensable in pancreatic β-cells for normal Ca²⁺ dynamics and insulin secretion. Cell calcium 29 26769314
2020 Loss of Two-Pore Channel 2 (TPC2) Expression Increases the Metastatic Traits of Melanoma Cells by a Mechanism Involving the Hippo Signalling Pathway and Store-Operated Calcium Entry. Cancers 27 32846966
2014 NAADP/TPC2/Ca(2+) Signaling Inhibits Autophagy. Communicative & integrative biology 26 24753792
2017 Ca2+ release via two-pore channel type 2 (TPC2) is required for slow muscle cell myofibrillogenesis and myotomal patterning in intact zebrafish embryos. Developmental biology 25 28390800
2014 Absence of intracellular ion channels TPC1 and TPC2 leads to mature-onset obesity in male mice, due to impaired lipid availability for thermogenesis in brown adipose tissue. Endocrinology 24 25545384
2022 Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! Cells 23 36139381
2022 Targeting TPC2 sensitizes acute lymphoblastic leukemia cells to chemotherapeutics by impairing lysosomal function. Cell death & disease 20 35915060
2012 Two-pore channel 2 (TPC2) modulates store-operated Ca(2+) entry. Biochimica et biophysica acta 16 23077736
2017 Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions. The Journal of biological chemistry 14 29084844
2023 Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation. Neurobiology of disease 13 36708960
2025 Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease. The Journal of cell biology 11 40279672
2020 TPC2-mediated Ca2+ signaling is required for axon extension in caudal primary motor neurons in zebrafish embryos. Journal of cell science 10 32546534
2023 Optical profiling of autonomous Ca2+ nanodomains generated by lysosomal TPC2 and TRPML1. Cell calcium 7 37742482
2025 A patient with TPCN2-related hypopigmentation and ocular phenotype. European journal of human genetics : EJHG 6 39809949
2023 A novel gain of function mutation in TPC2 reiterates pH-pigmentation interplay: Emerging role of ionic homeostasis as a master pigmentation regulator. Cell calcium 6 36841139
2023 A commentary on the inhibition of human TPC2 channel by the natural flavonoid naringenin: Methods, experiments, and ideas. Biomolecular concepts 6 37677148
2021 TPC2 targeting evolution: Leveraging therapeutic opportunities for cancer. Cell chemical biology 6 34416140
2023 Rac1 and Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons. Journal of cell science 5 36744839
2025 Glucose deprivation-restoration induces labile iron overload and ferroptosis in renal tubules through V-ATPase-mTOR axis-mediated ferritinophagy and iron release by TPC2. Free radical biology & medicine 3 40379157
2024 Deletion of Dictyostelium tpc2 gene forms multi-tipped structures, regulates autophagy and cell-type patterning. Biology of the cell 3 38537110
2025 Lysosomal TPC2 channel as a new target of chlorpromazine and clomipramine to induce protective autophagy in L-BMAA-induced neurodegeneration. Biochemical pharmacology 2 40796055
2025 Small molecule agonist TPC2-A1-N increases intracellular Ca2+ independent of two-pore channels. The Journal of biological chemistry 1 40784451
2025 OCA2 deficiency enhances TPC2 channel activity to reduce melanosomal pH and pigment production. The Journal of investigative dermatology 1 41443368
2024 TPC2 controls MITF expression and metastasis in melanoma. Cell calcium 1 39740384
2019 [Expression of Lysosomal Membrane Proteins LAMP1, TPC1 and TPC2 in Acute Myeloid Leukemia Cells and Its Clinical Significance]. Zhongguo shi yan xue ye xue za zhi 1 31418355
2026 Activation of TPC2 amplifies lysosome-mitochondria calcium transfer to regulate energetic stress responses. bioRxiv : the preprint server for biology 0 41867847
2026 Inhibition of endolysosomal two-pore channel 2 (TPC2) induces osteoblast differentiation and matrix mineralization while targeting autophagy. Journal of endocrinological investigation 0 42090110
2026 Auditory brainstem response in pigs: normative data and insights from TPC2 knockout models. Hearing research 0 42114217
2026 Regulation of Ferroptosis Sensitivity in Hepatocellular Carcinoma Cells by Lysosomal Ion Channels TPC2 and TRPML1. Antioxidants (Basel, Switzerland) 0 42193240
2026 TPC2 regulates proteomic remodeling, bioenergetic phenotypes, and mitochondrial stress adaptation in melanoma. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 0 42243615
2025 Polymethoxyflavones from Kaempferia parviflora stimulate melanogenesis by blocking the TPC2 channel. Scientific reports 0 41254057
2024 Hypoxia-induced TPC2 transcription and glycosylation aggravates pulmonary arterial hypertension by blocking autophagy flux. Scientific reports 0 39732974

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