{"gene":"TRPM2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"LTRPC2/TRPM2 functions as a calcium-permeable cation channel specifically gated by free intracellular ADP-ribose (ADPR). The C-terminal NUDT9 homology domain binds ADPR and possesses intrinsic ADPR pyrophosphatase activity. Whole-cell and single-channel recordings in HEK-293 cells expressing LTRPC2 confirmed ADPR-gated Ca2+-permeable cation currents matching those of native U937 monocytes.","method":"Whole-cell and single-channel patch-clamp electrophysiology; biochemical identification of NUDT9 homology domain; heterologous expression in HEK-293 cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro channel reconstitution with biochemical domain identification, replicated in native cells","pmids":["11385575"],"is_preprint":false},{"year":2001,"finding":"TRPM2 mediates Ca2+ influx into immunocytes (Jurkat T cells and RBL cells) and is directly activated by intracellular ADPR and NAD as Ca2+-permeable nonselective cation channel. ATP suppresses this activation, establishing ATP as an endogenous negative regulator.","method":"Whole-cell patch-clamp, Ca2+ imaging, heterologous expression","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological characterization in multiple cell types with defined ligand pharmacology","pmids":["11509734"],"is_preprint":false},{"year":2002,"finding":"TRPM2 is activated by H2O2 and agents generating reactive oxygen/nitrogen species, conferring susceptibility to cell death. Sensitivity to redox state modifiers is attributable to agonistic binding of NAD+ to the MutT (Nudix) motif. Arachidonic acid and Ca2+ are positive co-regulators. Antisense knockdown reduces H2O2- and TNFα-induced Ca2+ influx and cell death.","method":"Whole-cell patch-clamp, Ca2+ imaging, antisense oligonucleotide knockdown, heterologous expression in HEK cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, loss-of-function), replicated by multiple labs","pmids":["11804595"],"is_preprint":false},{"year":2002,"finding":"H2O2 activation of TRPM2 is independent of ADPR; a splice variant lacking amino acids 1292–1325 in the C-terminus still responds to H2O2 but not to ADPR, demonstrating separable activation mechanisms. H2O2-induced currents develop slowly with a characteristic delay, distinct from ADPR-induced currents.","method":"Whole-cell patch-clamp, Ca2+ imaging, splice variant cloning from neutrophil granulocytes, heterologous expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with natural splice variant, single lab but two orthogonal methods","pmids":["11960981"],"is_preprint":false},{"year":2003,"finding":"A short isoform of TRPM2 (TRPM2-S) consisting of the N-terminus and first two transmembrane domains directly interacts with full-length TRPM2-L via co-immunoprecipitation, localizes to the plasma membrane, suppresses H2O2-induced Ca2+ influx through TRPM2-L, and inhibits susceptibility to H2O2-induced apoptosis.","method":"Co-immunoprecipitation, confocal microscopy, Ca2+ flux assays, cell death assays, heterologous expression in HEK293T cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional Ca2+ influx assay and cell death assay, single lab","pmids":["12594222"],"is_preprint":false},{"year":2006,"finding":"Cyclic ADP-ribose (cADPR) and NAADP strongly activate natively expressed TRPM2 channels in Jurkat T cells. Their activity is partially suppressed by the ADPR antagonist AMP, suggesting mobilization of endogenous ADPR. Remaining activity is suppressed by 8-Br-cADPR, indicating cADPR and NAADP share a common binding site on TRPM2 and act as direct co-activators in synergy with ADPR.","method":"Whole-cell patch-clamp in Jurkat T cells, pharmacological dissection with AMP and 8-Br-cADPR antagonists","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — native cell electrophysiology with pharmacological dissection, single lab","pmids":["16585058"],"is_preprint":false},{"year":2011,"finding":"In dendritic cells, TRPM2 localizes to endolysosomal vesicles (rather than the plasma membrane) and functions as a lysosomal Ca2+ release channel contributing to chemokine-induced Ca2+ signaling and directional migration. TRPM2 deficiency (siRNA and KO mice) impairs DC maturation, chemotaxis, and in vivo bacterial-induced DC trafficking. In contrast, in neutrophils TRPM2 localizes to the plasma membrane.","method":"siRNA knockdown, TRPM2 knockout mice, confocal microscopy subcellular fractionation, Ca2+ imaging, chemotaxis assays, in vivo bacterial infection model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal loss-of-function (siRNA + KO), direct localization, in vitro and in vivo functional readouts","pmids":["21753080"],"is_preprint":false},{"year":2014,"finding":"TRPM2 mediates ischemic kidney injury through RAC1. Following ischemia, TRPM2 promotes RAC1 activation; active RAC1 physically interacts with TRPM2 (co-IP) and increases TRPM2 expression at the cell membrane, creating a feedforward loop that amplifies NADPH oxidase-dependent oxidant stress. Effects are attributed to TRPM2 in parenchymal (proximal tubule) cells, not hematopoietic cells, shown by chimeric mice.","method":"TRPM2 knockout mice, chimeric bone-marrow transplant mice, co-immunoprecipitation of RAC1–TRPM2, NADPH oxidase activity assays, RAC1 inhibition in vivo, kidney function and histology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of RAC1-TRPM2, multiple KO models, in vivo mechanistic dissection","pmids":["25295536"],"is_preprint":false},{"year":2014,"finding":"TRPM2 channels are responsible for Ca2+ entry in hepatocytes during acetaminophen overdose. Acetaminophen activates a cation current identical to that activated by H2O2 or intracellular ADPR; siRNA knockdown of TRPM2 inhibits both acetaminophen- and H2O2-induced currents. TRPM2 KO mice show significantly reduced acetaminophen-induced liver damage.","method":"Whole-cell patch-clamp in primary hepatocytes, siRNA knockdown, TRPM2 KO mice, liver enzyme assays and histology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct electrophysiology, siRNA loss-of-function, and genetic KO with in vivo organ injury readout","pmids":["24569808"],"is_preprint":false},{"year":2015,"finding":"TRPM2 channels in pancreatic β-cells conduct both Ca2+ and Zn2+; H2O2 activation increases cytosolic Zn2+ released from lysosomes, which express TRPM2 channels. Zn2+ chelation alone prevents β-cell apoptosis, indicating Zn2+ (not Ca2+) is the primary cytotoxic signal. Ca2+-potentiated lysosomal Zn2+ release underlies ROS-induced β-cell death; TRPM2 KO protects against STZ-induced hyperglycemia.","method":"Fluorescent Zn2+ and Ca2+ imaging, Zn2+ chelation, TRPM2 KO mice (STZ model), patch-clamp, lysosome TRPM2 localization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, chelation, genetic KO with in vivo diabetes model)","pmids":["25562606"],"is_preprint":false},{"year":2015,"finding":"TRPM2 regulates GSK-3 phosphorylation in the brain: TRPM2 activation induces dephosphorylation of GSK-3 via calcineurin, a Ca2+-dependent phosphatase. A BD-associated loss-of-function mutation D543E fails to dephosphorylate GSK-3. TRPM2-deficient mice show elevated phospho-GSK-3 and BD-related behaviors that are insensitive to lithium.","method":"TRPM2 KO mice, D543E mutant overexpression, biochemical GSK-3 phosphorylation assays, calcineurin inhibitor pharmacology, behavioral tests, EEG","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, site-directed mutant, pharmacological dissection of calcineurin pathway, multiple functional readouts","pmids":["26311765"],"is_preprint":false},{"year":2017,"finding":"ADPR-induced activation of TRPM2 critically depends on hydrogen bonding of residues Arg1433 and Tyr1349 in the NUDT9H domain with the terminal ribose of ADPR. All ADPR analogues modified at the terminal ribose lost agonist activity; mutagenesis of Arg1433 and Tyr1349 abrogated channel activation, identifying these as key gating determinants.","method":"Synthetic ADPR analogue library, whole-cell patch-clamp, site-directed mutagenesis of NUDT9H domain, structure-activity relationship analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with chemical biology (SAR) in electrophysiological assay, single lab","pmids":["28515263"],"is_preprint":false},{"year":2017,"finding":"Endothelial TRPM2 is required for PMN-induced transendothelial neutrophil migration. Neutrophil-derived ROS activates ADPR generation in endothelial cells, which gates TRPM2 to mediate Ca2+ entry; this causes VE-cadherin phosphorylation and disassembly of adherens junctions, opening paracellular pathways. Expression of ADPR-insensitive TRPM2 C1008A mutant or PARP silencing prevented PMN transmigration.","method":"Conditional EC-specific TRPM2 knockout mice, ADPR-insensitive mutant overexpression, PARP silencing, Ca2+ imaging, permeability assays, LPS challenge in vivo","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, dominant-negative mutant, in vivo and in vitro mechanistic dissection with defined molecular pathway","pmids":["28790198"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of zebrafish TRPM2 in apo (closed) and ADPR/Ca2+-bound (open) states reveal: the NUDT9-H domain hangs beneath the MHR1/2 domain; ADPR binds to a bi-lobed site in the MHR1/2 domain; Ca2+ binding further engages transmembrane helices and the TRP helix to open the gate. This defines the structural mechanism of concerted ADPR+Ca2+ activation.","method":"Cryo-electron microscopy structural determination of apo and ligand-bound states","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of two functional states providing direct mechanistic insight, published in Nature","pmids":["30250252"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of human TRPM2 alone, with ADPR, and with ADPR+Ca2+ show that NUDT9H forms both intra- and intersubunit interactions with MHR1/2/3 in the apo state; ADPR binding causes rotation of MHR1/2 and disruption of intersubunit interactions; Ca2+ binding further engages transmembrane helices and the TRP helix causing MHR arm and lower gating pore conformational changes to open the channel.","method":"Cryo-electron microscopy of three distinct states of human TRPM2","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM of human channel in three states, independent replication of zebrafish study","pmids":["30467180"],"is_preprint":false},{"year":2017,"finding":"Zn2+-induced TRPM2 channel activation in microglial cells proceeds via PKC/NADPH oxidase (NOX)-mediated ROS generation → PARP-1 stimulation → ADPR production → TRPM2 gating. TRPM2-mediated Ca2+ entry then triggers a PYK2/MEK/ERK positive feedback loop that amplifies further TRPM2 activation and drives Ca2+ overloading and cell death.","method":"TRPM2 KO cells, PARP inhibitors (PJ34, DPQ), NOX inhibitors, PKC inhibitor, PYK2 inhibitor, MEK/ERK inhibitor, Ca2+ imaging, cell viability assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TRPM2 KO plus multi-step pharmacological dissection, single lab","pmids":["28322340"],"is_preprint":false},{"year":2019,"finding":"Invertebrate TRPM2 (Nematostella vectensis, nvTRPM2) has catalytically active NUDT9H ADPRase activity, whereas vertebrate TRPM2 (including human) has vestigial (inactive) Nudix motifs due to sequence changes that emerged simultaneously with pore inactivation in early vertebrates. The ADPRase activity of nvTRPM2 is uncoupled from channel gating, demonstrating the enzymatic and channel functions are separable.","method":"Comparative sequence analysis, ADPRase activity assays of isolated NUDT9H domains, patch-clamp electrophysiology of nvTRPM2 and drTRPM2 channels with mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution, channel electrophysiology, and mutagenesis across multiple species in one study","pmids":["30938679"],"is_preprint":false},{"year":2018,"finding":"A novel calmodulin (CaM)-binding motif in the NudT9H domain of TRPM2 binds Ca2+-CaM upon partial thermal unfolding at temperatures >35°C, preventing further destabilization. Patch-clamp measurements of full-length TRPM2 indicate this CaM-binding site contributes to the temperature sensitivity of TRPM2.","method":"Biophysical characterization of CaM binding (ITC, NMR, crystallography), patch-clamp electrophysiology of full-length TRPM2","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural and biophysical binding data combined with functional patch-clamp, single lab","pmids":["30584900"],"is_preprint":false},{"year":2020,"finding":"TRPM2 is expressed in neural stem cells and regulates neural progenitor cell (NPC) self-renewal in response to hyperthermia by targeting SP5 (specificity protein 5) via inhibiting phosphorylation of β-catenin and increasing β-catenin expression. TRPM2 KD/KO reduces NPC proliferation and increases premature neuron differentiation; constitutive TRPM2 or SP5 expression partly rescues the deficit.","method":"TRPM2 knockdown and knockout in mouse embryos, neural stem cell culture, immunofluorescence, Western blot, rescue experiments with TRPM2 and SP5 overexpression","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus rescue experiments with defined signaling pathway, single lab","pmids":["31911949"],"is_preprint":false},{"year":2021,"finding":"TRPM2 physically associates with extrasynaptic NMDARs; this interaction promotes surface expression of extrasynaptic NMDARs and enhances NMDAR activity upon ischemic insults, exacerbating excitotoxic neuronal death. A membrane-permeable peptide targeting the NMDAR-interacting motif on TRPM2 uncouples the interaction and protects neurons in vitro and mice in vivo from ischemic injury.","method":"Co-immunoprecipitation of TRPM2-NMDAR complex, surface biotinylation, NMDAR current recordings, peptide disruption in vitro and in vivo (MCAO mouse model), neuronal cell death assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional surface expression analysis, peptide disruption with in vivo validation, multiple orthogonal methods","pmids":["35421327"],"is_preprint":false},{"year":2022,"finding":"TRPM2 and CD36 activate each other in a feedforward manner in macrophages: oxLDL and TSP1 activation of CD36 induces TRPM2 activity, and TRPM2 deletion suppresses CD36 signaling cascade activation. Global and macrophage-specific Trpm2 deletion protects ApoE-KO mice from atherosclerosis by reducing oxLDL uptake, foam cell formation, and inflammatory responses.","method":"Global and macrophage-specific conditional TRPM2 KO in ApoE-/- mice, cultured macrophage Ca2+ measurements, CD36 signaling assays, atherosclerotic plaque analysis","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO, mechanistic TRPM2–CD36 interaction assays, in vivo and in vitro orthogonal evidence","pmids":["35445217"],"is_preprint":false},{"year":2021,"finding":"LncRNA lncTRPM2-AS prevents TRIM21-mediated ubiquitination of TRPM2 protein at K1218, stabilizing TRPM2. LncTRPM2-AS silencing enhances TRIM21–TRPM2 interaction, increases ubiquitin-mediated TRPM2 degradation, decreases intracellular Ca2+ and ROS, and increases autophagy-induced macrophage apoptosis.","method":"RNA immunoprecipitation, mass spectrometry, co-IP of TRPM2-TRIM21, ubiquitination assays with K1218 mutation analysis, Ca2+ and ROS measurements, siRNA knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay with mutant, and functional Ca2+/ROS readouts in single lab study","pmids":["34903714"],"is_preprint":false},{"year":2023,"finding":"Bilirubin directly gates TRPM2 channel opening, independent of canonical intracellular ADPR or Ca2+ agonists, binding to a cavity also recognized by the antagonist A23. A knock-in loss-of-binding mutation D1066A effectively antagonizes ischemic neurotoxicity in mice, defining bilirubin as a novel direct TRPM2 agonist contributing to a feed-forward injury cycle in stroke.","method":"Patch-clamp electrophysiology with bilirubin and metabolites, competitive binding assays, TRPM2 KO mice, TRPM2-D1066A knock-in mice, ischemic stroke (MCAO) model in vivo","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct electrophysiological demonstration of gating, site-directed knock-in mutagenesis, in vivo ischemia model, multiple orthogonal methods","pmids":["36921602"],"is_preprint":false},{"year":2023,"finding":"TRPM2-mediated Ca2+ influx causes mitochondrial Ca2+ accumulation (via the mitochondrial Ca2+ uniporter, MCU) and increases ALOX12 expression, leading to mitochondrial lipid peroxidation and ferroptosis in hepatocytes during ischemia-reperfusion injury. TRPM2 inhibition or Ca2+ depletion suppresses ALOX12 upregulation and reduces ferroptotic liver injury.","method":"TRPM2 KO mice (hepatic IR model), mitochondrial Ca2+ imaging, ALOX12 expression analysis, ferroptosis markers, RSL3 treatment, MCU inhibitor, TRPM2 inhibitor","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic dissection of Ca2+→MCU→ALOX12 pathway, single lab","pmids":["37275121"],"is_preprint":false},{"year":2023,"finding":"TRPM2 knockout exacerbates cisplatin-induced acute kidney injury by blocking Ca2+-dependent autophagy: TRPM2 deficiency prevents cisplatin-induced Ca2+ influx, causing upregulation of AKT-mTOR signaling that inhibits autophagy, worsening mitochondrial damage and apoptosis. mTOR inhibitor treatment rescues the phenotype in TRPM2-KO mice.","method":"TRPM2 KO mice and primary cells, RNA sequencing, Ca2+ flux measurement, AKT-mTOR pathway analysis, mTOR inhibitor rescue, mitochondrial ROS and apoptosis assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with mechanistic pathway rescue, single lab, multiple readouts","pmids":["37649595"],"is_preprint":false},{"year":2022,"finding":"TRPM2 promotes neuroblastoma cell survival through Ca2+-dependent regulation of master transcription factors FOXM1 and E2F1/2. TRPM2 deletion reduces FOXM1 binding to promoters of cell cycle genes (Cyclin B1, CDK1, PLK1, CKS1) and DNA repair genes. Ca2+-impermeable mutant E960D fails to restore viability, establishing Ca2+ permeability as essential. FOXM1 overexpression alone restores viability.","method":"CRISPR TRPM2 deletion, RNA sequencing, RT-qPCR, ChIP (FOXM1 promoter binding), Western blot, cell cycle analysis, rescue with WT vs. E960D Ca2+-impermeable mutant, FOXM1 overexpression rescue","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR KO, ChIP, mutant rescue, and RNA sequencing in single comprehensive study, multiple orthogonal methods","pmids":["35428820"],"is_preprint":false},{"year":2020,"finding":"TRPM2 is abundantly expressed in lysosomes/autolysosomes of vascular smooth muscle cells and facilitates lysosomal acidification required for autophagic degradation. TRPM2 knockout reduces starvation-induced lysosomal acidification, autophagic flux, and consequent cell death, identifying lysosomal TRPM2 as a regulator of the late (degradation) stage of autophagy.","method":"TRPM2 KO mouse aortic smooth muscle cells, lysosomal/autolysosomal fractionation, immunofluorescence co-localization, lysosomal pH measurement, autophagic flux assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization combined with KO functional autophagy readout, single lab","pmids":["33244095"],"is_preprint":false},{"year":2021,"finding":"TRPM2 silencing in TRPM2 stabilizes HIF-1α and Nrf2 proteins via inhibiting their ubiquitination (co-immunoprecipitation), protecting gastric cancer cells from ferroptosis inducers Erastin and RSL3. Activation of HIF-1α impairs ferroptosis after TRPM2 knockdown.","method":"siRNA knockdown, co-immunoprecipitation for HIF-1α/Nrf2 ubiquitination, GSH/GPx/ROS/lipid peroxidation assays, cell viability assays","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of ubiquitination plus functional rescue, single lab","pmids":["36238268"],"is_preprint":false},{"year":2024,"finding":"In osteoarthritis chondrocytes, IL-1β upregulates TRPM2 expression via NF-κB-p65 binding to the Trpm2 promoter (validated by ChIP-PCR and ChIP-qPCR). TRPM2-mediated Ca2+ influx causes mitochondrial Ca2+ accumulation → mitochondrial DNA release → cGAS-STING → NF-κB activation, forming a pathological feedforward loop. TRPM2 KO and Ca2+ chelation with BAPTA-AM attenuate OA progression.","method":"TRPM2 KO mice (DMM model), ChIP-qPCR for NF-κB-p65 at Trpm2 promoter, siRNA/overexpression in chondrocytes, cGAS-STING pathway analysis, BAPTA-AM Ca2+ chelation in vivo","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation of transcriptional regulation, genetic KO, pathway dissection, single lab","pmids":["39505144"],"is_preprint":false}],"current_model":"TRPM2 is a Ca2+-permeable non-selective cation channel with a C-terminal NUDT9-H domain that binds intracellular ADP-ribose (ADPR) to gate the channel; cryo-EM structures reveal that ADPR binding to MHR1/2 and subsequent Ca2+ binding to the transmembrane/TRP-helix region drive concerted conformational changes that open the pore, while oxidative stress activates the channel via PARP-dependent ADPR generation; the channel localizes to the plasma membrane or lysosomal membranes depending on cell type to mediate Ca2+ influx or lysosomal Ca2+/Zn2+ release, respectively, engaging downstream cascades including calcineurin/GSK-3, FOXM1/E2F1 transcription, RAC1/NADPH oxidase, TRPM2–CD36 feedforward signaling, and TRPM2–NMDAR physical coupling, thereby controlling immune cell function, insulin secretion, neuronal survival, synaptic plasticity, and cell death in response to oxidative stress."},"narrative":{"mechanistic_narrative":"TRPM2 is a Ca2+-permeable non-selective cation channel that converts oxidative and metabolic stress signals into intracellular Ca2+ (and Zn2+) fluxes governing immune cell function, neuronal survival, and cell death [PMID:11385575, PMID:11509734, PMID:11804595]. The channel is gated by intracellular ADP-ribose binding to its C-terminal NUDT9 homology domain, which also possesses intrinsic ADPR pyrophosphatase activity, while NAD+, cADPR, and NAADP act as co-activators and ATP serves as an endogenous negative regulator [PMID:11385575, PMID:11509734, PMID:16585058]. Oxidative activation by H2O2 proceeds in part through a route separable from direct ADPR gating, and ROS-driven signaling engages PARP-dependent ADPR generation to open the channel [PMID:11804595, PMID:11960981, PMID:28790198, PMID:28322340]. Cryo-EM structures of zebrafish and human TRPM2 define the gating mechanism: ADPR binds a bi-lobed site in the MHR1/2 domain causing rotation and disruption of intersubunit contacts, and subsequent Ca2+ binding engages the transmembrane helices and TRP helix to open the pore in a concerted fashion [PMID:30250252, PMID:30467180]; specific NUDT9H residues (Arg1433, Tyr1349) hydrogen-bond the terminal ribose of ADPR as key gating determinants [PMID:28515263]. Notably, the enzymatic ADPRase activity is vestigial in vertebrate channels and is dispensable for, and separable from, channel gating [PMID:30938679]. TRPM2 localizes either to the plasma membrane or to endolysosomal membranes depending on cell type, mediating Ca2+ influx in neutrophils or lysosomal Ca2+/Zn2+ release and lysosomal acidification in dendritic cells, β-cells, and smooth muscle [PMID:21753080, PMID:25562606, PMID:33244095]. Downstream, TRPM2-dependent Ca2+ entry drives calcineurin-mediated GSK-3 dephosphorylation in brain [PMID:26311765], FOXM1/E2F transcriptional programs supporting tumor cell survival [PMID:35428820], a RAC1/NADPH oxidase feedforward loop in kidney injury [PMID:25295536], TRPM2–CD36 feedforward signaling in atherogenic macrophages [PMID:35445217], and physical coupling to extrasynaptic NMDARs that exacerbates ischemic excitotoxicity [PMID:35421327]. Channel abundance is set post-translationally by TRIM21-mediated ubiquitination at K1218, which is antagonized by lncTRPM2-AS [PMID:34903714]. Through these outputs TRPM2 contributes to cell-death pathways including Zn2+-driven β-cell apoptosis, mitochondrial Ca2+/ALOX12-dependent ferroptosis, and cGAS-STING inflammatory loops [PMID:25562606, PMID:37275121, PMID:39505144]. A loss-of-function variant (D543E) failing to dephosphorylate GSK-3 links TRPM2 to bipolar disorder-related phenotypes [PMID:26311765].","teleology":[{"year":2001,"claim":"Established TRPM2 as a Ca2+-permeable cation channel gated by intracellular ADP-ribose, defining its core molecular identity and a built-in NUDT9 sensor domain.","evidence":"Whole-cell/single-channel patch-clamp and biochemical domain identification in HEK-293 cells and native U937 monocytes; parallel Ca2+ imaging in Jurkat/RBL cells","pmids":["11385575","11509734"],"confidence":"High","gaps":["Did not resolve whether NUDT9H enzymatic activity contributes to gating","Endogenous source of activating ADPR not defined"]},{"year":2002,"claim":"Connected TRPM2 to oxidative stress by showing H2O2/ROS activation and redox/NAD+ sensitivity confer susceptibility to cell death, with an activation route separable from direct ADPR gating.","evidence":"Patch-clamp, Ca2+ imaging, antisense knockdown in HEK cells; splice variant lacking aa1292-1325 responding to H2O2 but not ADPR","pmids":["11804595","11960981"],"confidence":"High","gaps":["Molecular intermediary linking H2O2 to channel gating not identified","Relationship between the H2O2 route and endogenous ADPR generation unresolved"]},{"year":2003,"claim":"Identified a dominant-negative short isoform (TRPM2-S) that heteromerizes with full-length channel to suppress Ca2+ influx and apoptosis, revealing endogenous regulation of channel output.","evidence":"Co-immunoprecipitation, confocal microscopy, Ca2+ flux and cell death assays in HEK293T cells","pmids":["12594222"],"confidence":"High","gaps":["Physiological contexts where TRPM2-S sets channel activity not defined","Stoichiometry of suppression unknown"]},{"year":2006,"claim":"Broadened the ligand landscape by showing cADPR and NAADP act as direct co-activators sharing a binding site and synergizing with ADPR in native channels.","evidence":"Whole-cell patch-clamp with AMP and 8-Br-cADPR antagonist dissection in Jurkat T cells","pmids":["16585058"],"confidence":"Medium","gaps":["Single lab, pharmacological inference of shared site","Structural basis of cADPR/NAADP binding not determined"]},{"year":2011,"claim":"Revealed cell-type-dependent localization, showing TRPM2 acts as a lysosomal Ca2+ release channel in dendritic cells controlling chemotaxis versus a plasma membrane channel in neutrophils.","evidence":"siRNA, TRPM2 KO mice, subcellular fractionation, Ca2+ imaging, chemotaxis and in vivo bacterial trafficking assays","pmids":["21753080"],"confidence":"High","gaps":["Determinants of plasma membrane versus lysosomal targeting unknown","How lysosomal gating ligands are supplied not defined"]},{"year":2014,"claim":"Demonstrated TRPM2 as a driver of organ injury through distinct downstream effectors, including a RAC1/NADPH oxidase feedforward loop in kidney and ROS-coupled Ca2+ entry in acetaminophen hepatotoxicity.","evidence":"TRPM2 KO and chimeric mice, RAC1-TRPM2 co-IP, NADPH oxidase assays (kidney); primary hepatocyte patch-clamp, siRNA, KO mice (liver)","pmids":["25295536","24569808"],"confidence":"High","gaps":["Whether RAC1-TRPM2 coupling generalizes beyond proximal tubule unclear","Direct molecular interface of RAC1-TRPM2 not mapped"]},{"year":2015,"claim":"Defined Zn2+ (not Ca2+) as the cytotoxic species in β-cell death and showed calcineurin-dependent GSK-3 regulation, linking TRPM2 to diabetes and to a bipolar disorder-associated loss-of-function variant.","evidence":"Zn2+/Ca2+ imaging, chelation, TRPM2 KO mice in STZ model (β-cells); KO mice, D543E mutant, calcineurin pharmacology, behavior/EEG (brain)","pmids":["25562606","26311765"],"confidence":"High","gaps":["Source/transport route of lysosomal Zn2+ via TRPM2 not fully resolved","Mechanism connecting calcineurin to behavioral phenotypes incomplete"]},{"year":2017,"claim":"Mapped key ADPR-gating residues and a CaM-binding temperature sensor in NUDT9H, and established endothelial TRPM2 as a PARP/ADPR-gated mediator of neutrophil transendothelial migration.","evidence":"ADPR analogue SAR with Arg1433/Tyr1349 mutagenesis; CaM-binding biophysics + patch-clamp; EC-specific KO, ADPR-insensitive C1008A mutant, PARP silencing, permeability and LPS assays; microglial PARP/NOX/PYK2/MEK-ERK pharmacology","pmids":["28515263","30584900","28790198","28322340"],"confidence":"High","gaps":["How thermal sensing integrates with ligand gating in vivo unclear","Quantitative contribution of CaM to physiological temperature responses not defined"]},{"year":2018,"claim":"Resolved the structural gating mechanism by cryo-EM, showing ADPR binding to MHR1/2 and concerted Ca2+ binding at the transmembrane/TRP-helix region open the pore in both zebrafish and human channels.","evidence":"Cryo-EM of apo, ADPR-bound, and ADPR+Ca2+-bound states of zebrafish and human TRPM2","pmids":["30250252","30467180"],"confidence":"High","gaps":["Structural basis of the ADPR-independent H2O2 route not captured","Dynamics of NUDT9H repositioning during gating not time-resolved"]},{"year":2019,"claim":"Showed that vertebrate channel gating is uncoupled from NUDT9H catalysis, with vertebrate Nudix activity vestigial and channel/enzyme functions evolutionarily separable.","evidence":"Comparative sequence analysis, ADPRase assays of isolated NUDT9H, and patch-clamp/mutagenesis of invertebrate and zebrafish channels","pmids":["30938679"],"confidence":"High","gaps":["Physiological role, if any, of residual human NUDT9H activity unknown","Why pore and enzyme inactivation co-emerged mechanistically unexplained"]},{"year":2020,"claim":"Extended TRPM2 outputs to cell-fate transcriptional and developmental programs and to late-stage autophagy, linking channel Ca2+ flux to FOXM1/E2F survival programs, β-catenin/SP5 in neural progenitors, and lysosomal acidification.","evidence":"CRISPR KO, ChIP, Ca2+-impermeable E960D rescue (neuroblastoma); embryo KO/rescue with SP5 (NPCs); KO smooth muscle cells with lysosomal pH and autophagic flux assays","pmids":["35428820","31911949","33244095"],"confidence":"High","gaps":["Mechanism coupling Ca2+ to FOXM1/E2F activity not detailed","How TRPM2 controls lysosomal pH mechanistically unresolved"]},{"year":2021,"claim":"Established post-translational and partner-based control of TRPM2, including TRIM21/lncTRPM2-AS-regulated stability at K1218, HIF-1α/Nrf2 stabilization opposing ferroptosis, and physical coupling to extrasynaptic NMDARs driving excitotoxicity.","evidence":"RIP/MS, co-IP and ubiquitination assays with K1218 mutant; co-IP of HIF-1α/Nrf2 ubiquitination with viability assays; TRPM2-NMDAR co-IP, surface biotinylation, disruptive peptide in MCAO mice","pmids":["34903714","36238268","35421327"],"confidence":"High","gaps":["Generality of TRIM21-mediated turnover across tissues unknown","Molecular motif mediating TRPM2-NMDAR association only partly defined"]},{"year":2022,"claim":"Identified TRPM2–CD36 feedforward signaling in macrophages as a driver of atherosclerosis, expanding TRPM2's role in metabolic-inflammatory disease.","evidence":"Global and macrophage-specific conditional KO in ApoE-/- mice, macrophage Ca2+ and CD36 signaling assays, plaque analysis","pmids":["35445217"],"confidence":"High","gaps":["Molecular nature of TRPM2-CD36 mutual activation not structurally defined","Whether direct physical interaction underlies the feedforward loop unclear"]},{"year":2023,"claim":"Discovered bilirubin as a direct, ADPR/Ca2+-independent TRPM2 agonist and dissected mitochondrial Ca2+/ALOX12 ferroptosis and Ca2+/autophagy outputs in injury, broadening both the agonist repertoire and downstream death pathways.","evidence":"Patch-clamp with bilirubin, competitive binding, D1066A knock-in mice in MCAO; KO mice with MCU/ALOX12 ferroptosis dissection (liver IR); KO with AKT-mTOR/autophagy rescue (cisplatin AKI)","pmids":["36921602","37275121","37649595"],"confidence":"High","gaps":["Structural overlap of the bilirubin site with other ligand sites not fully mapped","Context determining protective versus detrimental TRPM2 roles in injury unresolved"]},{"year":2024,"claim":"Showed transcriptional induction of TRPM2 by NF-κB-p65 and a Ca2+/mitochondrial DNA/cGAS-STING feedforward loop in osteoarthritis, linking channel activity to inflammatory amplification.","evidence":"ChIP-qPCR at Trpm2 promoter, TRPM2 KO DMM mice, chondrocyte siRNA/overexpression, cGAS-STING pathway analysis, BAPTA-AM rescue","pmids":["39505144"],"confidence":"Medium","gaps":["Single lab; generality of the cGAS-STING loop to other tissues untested","How mitochondrial Ca2+ overload triggers mtDNA release mechanistically unclear"]},{"year":null,"claim":"The molecular basis of the ADPR-independent oxidative/H2O2 activation route and the determinants directing TRPM2 to plasma membrane versus lysosomal compartments remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure captures the H2O2-activated state","Trafficking signals controlling subcellular targeting not identified","Mechanism converting context-specific signals into protective versus cytotoxic Ca2+/Zn2+ output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,6,9,13,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,16]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6,9,26]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,9,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,9,23,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,12,20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24,26]}],"complexes":[],"partners":["TRPM2 (TRPM2-S ISOFORM)","RAC1","NMDAR","CD36","TRIM21","CALMODULIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94759","full_name":"Transient receptor potential cation channel subfamily M member 2","aliases":["Estrogen-responsive element-associated gene 1 protein","Long transient receptor potential channel 2","LTrpC-2","LTrpC2","Transient receptor potential channel 7","TrpC7","Transient receptor potential melastatin 2"],"length_aa":1503,"mass_kda":171.2,"function":"Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:12594222, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:20660597, PubMed:25620041, PubMed:27068538, PubMed:27383051, PubMed:28775320, PubMed:29745897, PubMed:30467180, PubMed:31513012, PubMed:34788616). Functions as a ligand-gated ion channel, gated by intracellular adenosine diphosphate ribose (ADP-ribose), Ca(2+), warm temperature, and oxidative stress (PubMed:19171771, PubMed:25620041, PubMed:28775320, PubMed:30467180). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate (PubMed:20650899, PubMed:25918360). Binding of ADP-ribose to the cytoplasmic Nudix domain causes a conformation change; the channel is primed but still requires Ca(2+) binding to trigger channel opening (PubMed:19171771, PubMed:25620041, PubMed:28775320, PubMed:29745897, PubMed:30467180). Extracellular Ca(2+) passes through the channel and increases channel activity (PubMed:19171771). Contributes to Ca(2+) release from intracellular stores in response to ADP-ribose (PubMed:19454650). Plays a role in numerous processes that involve signaling via intracellular Ca(2+) levels (Probable). Besides, mediates the release of lysosomal Zn(2+) stores in response to reactive oxygen species, leading to increased cytosolic Zn(2+) levels (PubMed:25562606, PubMed:27068538). Plays a role in mediating behavorial and physiological responses to moderate heat and thereby contributes to body temperature homeostasis. Plays a role in insulin secretion, a process that requires increased cytoplasmic Ca(2+) levels (By similarity). Required for normal IFNG and cytokine secretion and normal innate immune immunity in response to bacterial infection. Required for normal phagocytosis and cytokine release by macrophages exposed to zymosan (in vitro) (PubMed:22493272). Plays a role in dendritic cell differentiation and maturation, and in dendritic cell chemotaxis via its role in regulating cytoplasmic Ca(2+) levels (By similarity). Plays a role in the regulation of the reorganization of the actin cytoskeleton and filopodia formation in response to reactive oxygen species via its role in increasing cytoplasmic Ca(2+) and Zn(2+) levels (PubMed:27068538). Confers susceptibility to cell death following oxidative stress (PubMed:12594222, PubMed:25562606) Lacks cation channel activity. Does not mediate cation transport in response to oxidative stress or ADP-ribose Lacks cation channel activity and negatively regulates the channel activity of isoform 1. Negatively regulates susceptibility to cell death in reposponse to oxidative stress","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O94759/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPM2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPM2","total_profiled":1310},"omim":[{"mim_id":"616252","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 2; TCAF2","url":"https://www.omim.org/entry/616252"},{"mim_id":"616251","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 1; TCAF1","url":"https://www.omim.org/entry/616251"},{"mim_id":"612489","title":"RING FINGER PROTEIN 24; RNF24","url":"https://www.omim.org/entry/612489"},{"mim_id":"609633","title":"MAJOR AFFECTIVE DISORDER 3; MAFD3","url":"https://www.omim.org/entry/609633"},{"mim_id":"606678","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 8; TRPM8","url":"https://www.omim.org/entry/606678"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":19.0}],"url":"https://www.proteinatlas.org/search/TRPM2"},"hgnc":{"alias_symbol":["KNP3","LTRPC2","NUDT9L1","NUDT9H","EREG1"],"prev_symbol":["TRPC7"]},"alphafold":{"accession":"O94759","domains":[{"cath_id":"-","chopping":"66-124","consensus_level":"medium","plddt":75.8722,"start":66,"end":124},{"cath_id":"-","chopping":"129-165_204-329","consensus_level":"medium","plddt":85.3925,"start":129,"end":329},{"cath_id":"-","chopping":"510-541_557-579_618-742","consensus_level":"high","plddt":88.5962,"start":510,"end":742},{"cath_id":"-","chopping":"748-928_1062-1099","consensus_level":"medium","plddt":82.9433,"start":748,"end":1099},{"cath_id":"-","chopping":"937-1041","consensus_level":"high","plddt":78.6916,"start":937,"end":1041},{"cath_id":"3.90.79.10","chopping":"1242-1500","consensus_level":"medium","plddt":81.4557,"start":1242,"end":1500},{"cath_id":"1.20.5","chopping":"1144-1184","consensus_level":"medium","plddt":70.8966,"start":1144,"end":1184}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94759","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94759-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94759-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPM2","jax_strain_url":"https://www.jax.org/strain/search?query=TRPM2"},"sequence":{"accession":"O94759","fasta_url":"https://rest.uniprot.org/uniprotkb/O94759.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94759/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94759"}},"corpus_meta":[{"pmid":"11385575","id":"PMC_11385575","title":"ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11385575","citation_count":785,"is_preprint":false},{"pmid":"11804595","id":"PMC_11804595","title":"LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death.","date":"2002","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11804595","citation_count":686,"is_preprint":false},{"pmid":"11509734","id":"PMC_11509734","title":"Immunocyte Ca2+ influx system mediated by LTRPC2.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11509734","citation_count":389,"is_preprint":false},{"pmid":"11960981","id":"PMC_11960981","title":"Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. 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non-coding RNA TRPM2-AS as a potential biomarker for hepatocellular carcinoma.","date":"2017","source":"Irish journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/29081064","citation_count":19,"is_preprint":false},{"pmid":"36238268","id":"PMC_36238268","title":"Silencing TRPM2 enhanced erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins.","date":"2022","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36238268","citation_count":19,"is_preprint":false},{"pmid":"33931144","id":"PMC_33931144","title":"TRPM2 channel in oxidative stress-induced mitochondrial dysfunction and apoptotic cell death.","date":"2021","source":"Advances in protein chemistry and structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33931144","citation_count":18,"is_preprint":false},{"pmid":"30584900","id":"PMC_30584900","title":"Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30584900","citation_count":17,"is_preprint":false},{"pmid":"35428820","id":"PMC_35428820","title":"The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35428820","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49935,"output_tokens":7933,"usd":0.1344,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17523,"output_tokens":5961,"usd":0.11832,"stage2_stop_reason":"end_turn"},"total_usd":0.25272,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"LTRPC2/TRPM2 functions as a calcium-permeable cation channel specifically gated by free intracellular ADP-ribose (ADPR). The C-terminal NUDT9 homology domain binds ADPR and possesses intrinsic ADPR pyrophosphatase activity. Whole-cell and single-channel recordings in HEK-293 cells expressing LTRPC2 confirmed ADPR-gated Ca2+-permeable cation currents matching those of native U937 monocytes.\",\n      \"method\": \"Whole-cell and single-channel patch-clamp electrophysiology; biochemical identification of NUDT9 homology domain; heterologous expression in HEK-293 cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro channel reconstitution with biochemical domain identification, replicated in native cells\",\n      \"pmids\": [\"11385575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TRPM2 mediates Ca2+ influx into immunocytes (Jurkat T cells and RBL cells) and is directly activated by intracellular ADPR and NAD as Ca2+-permeable nonselective cation channel. ATP suppresses this activation, establishing ATP as an endogenous negative regulator.\",\n      \"method\": \"Whole-cell patch-clamp, Ca2+ imaging, heterologous expression\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological characterization in multiple cell types with defined ligand pharmacology\",\n      \"pmids\": [\"11509734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRPM2 is activated by H2O2 and agents generating reactive oxygen/nitrogen species, conferring susceptibility to cell death. Sensitivity to redox state modifiers is attributable to agonistic binding of NAD+ to the MutT (Nudix) motif. Arachidonic acid and Ca2+ are positive co-regulators. Antisense knockdown reduces H2O2- and TNFα-induced Ca2+ influx and cell death.\",\n      \"method\": \"Whole-cell patch-clamp, Ca2+ imaging, antisense oligonucleotide knockdown, heterologous expression in HEK cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, loss-of-function), replicated by multiple labs\",\n      \"pmids\": [\"11804595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"H2O2 activation of TRPM2 is independent of ADPR; a splice variant lacking amino acids 1292–1325 in the C-terminus still responds to H2O2 but not to ADPR, demonstrating separable activation mechanisms. H2O2-induced currents develop slowly with a characteristic delay, distinct from ADPR-induced currents.\",\n      \"method\": \"Whole-cell patch-clamp, Ca2+ imaging, splice variant cloning from neutrophil granulocytes, heterologous expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with natural splice variant, single lab but two orthogonal methods\",\n      \"pmids\": [\"11960981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A short isoform of TRPM2 (TRPM2-S) consisting of the N-terminus and first two transmembrane domains directly interacts with full-length TRPM2-L via co-immunoprecipitation, localizes to the plasma membrane, suppresses H2O2-induced Ca2+ influx through TRPM2-L, and inhibits susceptibility to H2O2-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, Ca2+ flux assays, cell death assays, heterologous expression in HEK293T cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional Ca2+ influx assay and cell death assay, single lab\",\n      \"pmids\": [\"12594222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cyclic ADP-ribose (cADPR) and NAADP strongly activate natively expressed TRPM2 channels in Jurkat T cells. Their activity is partially suppressed by the ADPR antagonist AMP, suggesting mobilization of endogenous ADPR. Remaining activity is suppressed by 8-Br-cADPR, indicating cADPR and NAADP share a common binding site on TRPM2 and act as direct co-activators in synergy with ADPR.\",\n      \"method\": \"Whole-cell patch-clamp in Jurkat T cells, pharmacological dissection with AMP and 8-Br-cADPR antagonists\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — native cell electrophysiology with pharmacological dissection, single lab\",\n      \"pmids\": [\"16585058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In dendritic cells, TRPM2 localizes to endolysosomal vesicles (rather than the plasma membrane) and functions as a lysosomal Ca2+ release channel contributing to chemokine-induced Ca2+ signaling and directional migration. TRPM2 deficiency (siRNA and KO mice) impairs DC maturation, chemotaxis, and in vivo bacterial-induced DC trafficking. In contrast, in neutrophils TRPM2 localizes to the plasma membrane.\",\n      \"method\": \"siRNA knockdown, TRPM2 knockout mice, confocal microscopy subcellular fractionation, Ca2+ imaging, chemotaxis assays, in vivo bacterial infection model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal loss-of-function (siRNA + KO), direct localization, in vitro and in vivo functional readouts\",\n      \"pmids\": [\"21753080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM2 mediates ischemic kidney injury through RAC1. Following ischemia, TRPM2 promotes RAC1 activation; active RAC1 physically interacts with TRPM2 (co-IP) and increases TRPM2 expression at the cell membrane, creating a feedforward loop that amplifies NADPH oxidase-dependent oxidant stress. Effects are attributed to TRPM2 in parenchymal (proximal tubule) cells, not hematopoietic cells, shown by chimeric mice.\",\n      \"method\": \"TRPM2 knockout mice, chimeric bone-marrow transplant mice, co-immunoprecipitation of RAC1–TRPM2, NADPH oxidase activity assays, RAC1 inhibition in vivo, kidney function and histology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of RAC1-TRPM2, multiple KO models, in vivo mechanistic dissection\",\n      \"pmids\": [\"25295536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM2 channels are responsible for Ca2+ entry in hepatocytes during acetaminophen overdose. Acetaminophen activates a cation current identical to that activated by H2O2 or intracellular ADPR; siRNA knockdown of TRPM2 inhibits both acetaminophen- and H2O2-induced currents. TRPM2 KO mice show significantly reduced acetaminophen-induced liver damage.\",\n      \"method\": \"Whole-cell patch-clamp in primary hepatocytes, siRNA knockdown, TRPM2 KO mice, liver enzyme assays and histology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct electrophysiology, siRNA loss-of-function, and genetic KO with in vivo organ injury readout\",\n      \"pmids\": [\"24569808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPM2 channels in pancreatic β-cells conduct both Ca2+ and Zn2+; H2O2 activation increases cytosolic Zn2+ released from lysosomes, which express TRPM2 channels. Zn2+ chelation alone prevents β-cell apoptosis, indicating Zn2+ (not Ca2+) is the primary cytotoxic signal. Ca2+-potentiated lysosomal Zn2+ release underlies ROS-induced β-cell death; TRPM2 KO protects against STZ-induced hyperglycemia.\",\n      \"method\": \"Fluorescent Zn2+ and Ca2+ imaging, Zn2+ chelation, TRPM2 KO mice (STZ model), patch-clamp, lysosome TRPM2 localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, chelation, genetic KO with in vivo diabetes model)\",\n      \"pmids\": [\"25562606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPM2 regulates GSK-3 phosphorylation in the brain: TRPM2 activation induces dephosphorylation of GSK-3 via calcineurin, a Ca2+-dependent phosphatase. A BD-associated loss-of-function mutation D543E fails to dephosphorylate GSK-3. TRPM2-deficient mice show elevated phospho-GSK-3 and BD-related behaviors that are insensitive to lithium.\",\n      \"method\": \"TRPM2 KO mice, D543E mutant overexpression, biochemical GSK-3 phosphorylation assays, calcineurin inhibitor pharmacology, behavioral tests, EEG\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, site-directed mutant, pharmacological dissection of calcineurin pathway, multiple functional readouts\",\n      \"pmids\": [\"26311765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADPR-induced activation of TRPM2 critically depends on hydrogen bonding of residues Arg1433 and Tyr1349 in the NUDT9H domain with the terminal ribose of ADPR. All ADPR analogues modified at the terminal ribose lost agonist activity; mutagenesis of Arg1433 and Tyr1349 abrogated channel activation, identifying these as key gating determinants.\",\n      \"method\": \"Synthetic ADPR analogue library, whole-cell patch-clamp, site-directed mutagenesis of NUDT9H domain, structure-activity relationship analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with chemical biology (SAR) in electrophysiological assay, single lab\",\n      \"pmids\": [\"28515263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endothelial TRPM2 is required for PMN-induced transendothelial neutrophil migration. Neutrophil-derived ROS activates ADPR generation in endothelial cells, which gates TRPM2 to mediate Ca2+ entry; this causes VE-cadherin phosphorylation and disassembly of adherens junctions, opening paracellular pathways. Expression of ADPR-insensitive TRPM2 C1008A mutant or PARP silencing prevented PMN transmigration.\",\n      \"method\": \"Conditional EC-specific TRPM2 knockout mice, ADPR-insensitive mutant overexpression, PARP silencing, Ca2+ imaging, permeability assays, LPS challenge in vivo\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, dominant-negative mutant, in vivo and in vitro mechanistic dissection with defined molecular pathway\",\n      \"pmids\": [\"28790198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of zebrafish TRPM2 in apo (closed) and ADPR/Ca2+-bound (open) states reveal: the NUDT9-H domain hangs beneath the MHR1/2 domain; ADPR binds to a bi-lobed site in the MHR1/2 domain; Ca2+ binding further engages transmembrane helices and the TRP helix to open the gate. This defines the structural mechanism of concerted ADPR+Ca2+ activation.\",\n      \"method\": \"Cryo-electron microscopy structural determination of apo and ligand-bound states\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of two functional states providing direct mechanistic insight, published in Nature\",\n      \"pmids\": [\"30250252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of human TRPM2 alone, with ADPR, and with ADPR+Ca2+ show that NUDT9H forms both intra- and intersubunit interactions with MHR1/2/3 in the apo state; ADPR binding causes rotation of MHR1/2 and disruption of intersubunit interactions; Ca2+ binding further engages transmembrane helices and the TRP helix causing MHR arm and lower gating pore conformational changes to open the channel.\",\n      \"method\": \"Cryo-electron microscopy of three distinct states of human TRPM2\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM of human channel in three states, independent replication of zebrafish study\",\n      \"pmids\": [\"30467180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zn2+-induced TRPM2 channel activation in microglial cells proceeds via PKC/NADPH oxidase (NOX)-mediated ROS generation → PARP-1 stimulation → ADPR production → TRPM2 gating. TRPM2-mediated Ca2+ entry then triggers a PYK2/MEK/ERK positive feedback loop that amplifies further TRPM2 activation and drives Ca2+ overloading and cell death.\",\n      \"method\": \"TRPM2 KO cells, PARP inhibitors (PJ34, DPQ), NOX inhibitors, PKC inhibitor, PYK2 inhibitor, MEK/ERK inhibitor, Ca2+ imaging, cell viability assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TRPM2 KO plus multi-step pharmacological dissection, single lab\",\n      \"pmids\": [\"28322340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Invertebrate TRPM2 (Nematostella vectensis, nvTRPM2) has catalytically active NUDT9H ADPRase activity, whereas vertebrate TRPM2 (including human) has vestigial (inactive) Nudix motifs due to sequence changes that emerged simultaneously with pore inactivation in early vertebrates. The ADPRase activity of nvTRPM2 is uncoupled from channel gating, demonstrating the enzymatic and channel functions are separable.\",\n      \"method\": \"Comparative sequence analysis, ADPRase activity assays of isolated NUDT9H domains, patch-clamp electrophysiology of nvTRPM2 and drTRPM2 channels with mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution, channel electrophysiology, and mutagenesis across multiple species in one study\",\n      \"pmids\": [\"30938679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A novel calmodulin (CaM)-binding motif in the NudT9H domain of TRPM2 binds Ca2+-CaM upon partial thermal unfolding at temperatures >35°C, preventing further destabilization. Patch-clamp measurements of full-length TRPM2 indicate this CaM-binding site contributes to the temperature sensitivity of TRPM2.\",\n      \"method\": \"Biophysical characterization of CaM binding (ITC, NMR, crystallography), patch-clamp electrophysiology of full-length TRPM2\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and biophysical binding data combined with functional patch-clamp, single lab\",\n      \"pmids\": [\"30584900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPM2 is expressed in neural stem cells and regulates neural progenitor cell (NPC) self-renewal in response to hyperthermia by targeting SP5 (specificity protein 5) via inhibiting phosphorylation of β-catenin and increasing β-catenin expression. TRPM2 KD/KO reduces NPC proliferation and increases premature neuron differentiation; constitutive TRPM2 or SP5 expression partly rescues the deficit.\",\n      \"method\": \"TRPM2 knockdown and knockout in mouse embryos, neural stem cell culture, immunofluorescence, Western blot, rescue experiments with TRPM2 and SP5 overexpression\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus rescue experiments with defined signaling pathway, single lab\",\n      \"pmids\": [\"31911949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPM2 physically associates with extrasynaptic NMDARs; this interaction promotes surface expression of extrasynaptic NMDARs and enhances NMDAR activity upon ischemic insults, exacerbating excitotoxic neuronal death. A membrane-permeable peptide targeting the NMDAR-interacting motif on TRPM2 uncouples the interaction and protects neurons in vitro and mice in vivo from ischemic injury.\",\n      \"method\": \"Co-immunoprecipitation of TRPM2-NMDAR complex, surface biotinylation, NMDAR current recordings, peptide disruption in vitro and in vivo (MCAO mouse model), neuronal cell death assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional surface expression analysis, peptide disruption with in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"35421327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPM2 and CD36 activate each other in a feedforward manner in macrophages: oxLDL and TSP1 activation of CD36 induces TRPM2 activity, and TRPM2 deletion suppresses CD36 signaling cascade activation. Global and macrophage-specific Trpm2 deletion protects ApoE-KO mice from atherosclerosis by reducing oxLDL uptake, foam cell formation, and inflammatory responses.\",\n      \"method\": \"Global and macrophage-specific conditional TRPM2 KO in ApoE-/- mice, cultured macrophage Ca2+ measurements, CD36 signaling assays, atherosclerotic plaque analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO, mechanistic TRPM2–CD36 interaction assays, in vivo and in vitro orthogonal evidence\",\n      \"pmids\": [\"35445217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA lncTRPM2-AS prevents TRIM21-mediated ubiquitination of TRPM2 protein at K1218, stabilizing TRPM2. LncTRPM2-AS silencing enhances TRIM21–TRPM2 interaction, increases ubiquitin-mediated TRPM2 degradation, decreases intracellular Ca2+ and ROS, and increases autophagy-induced macrophage apoptosis.\",\n      \"method\": \"RNA immunoprecipitation, mass spectrometry, co-IP of TRPM2-TRIM21, ubiquitination assays with K1218 mutation analysis, Ca2+ and ROS measurements, siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay with mutant, and functional Ca2+/ROS readouts in single lab study\",\n      \"pmids\": [\"34903714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Bilirubin directly gates TRPM2 channel opening, independent of canonical intracellular ADPR or Ca2+ agonists, binding to a cavity also recognized by the antagonist A23. A knock-in loss-of-binding mutation D1066A effectively antagonizes ischemic neurotoxicity in mice, defining bilirubin as a novel direct TRPM2 agonist contributing to a feed-forward injury cycle in stroke.\",\n      \"method\": \"Patch-clamp electrophysiology with bilirubin and metabolites, competitive binding assays, TRPM2 KO mice, TRPM2-D1066A knock-in mice, ischemic stroke (MCAO) model in vivo\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct electrophysiological demonstration of gating, site-directed knock-in mutagenesis, in vivo ischemia model, multiple orthogonal methods\",\n      \"pmids\": [\"36921602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRPM2-mediated Ca2+ influx causes mitochondrial Ca2+ accumulation (via the mitochondrial Ca2+ uniporter, MCU) and increases ALOX12 expression, leading to mitochondrial lipid peroxidation and ferroptosis in hepatocytes during ischemia-reperfusion injury. TRPM2 inhibition or Ca2+ depletion suppresses ALOX12 upregulation and reduces ferroptotic liver injury.\",\n      \"method\": \"TRPM2 KO mice (hepatic IR model), mitochondrial Ca2+ imaging, ALOX12 expression analysis, ferroptosis markers, RSL3 treatment, MCU inhibitor, TRPM2 inhibitor\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic dissection of Ca2+→MCU→ALOX12 pathway, single lab\",\n      \"pmids\": [\"37275121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRPM2 knockout exacerbates cisplatin-induced acute kidney injury by blocking Ca2+-dependent autophagy: TRPM2 deficiency prevents cisplatin-induced Ca2+ influx, causing upregulation of AKT-mTOR signaling that inhibits autophagy, worsening mitochondrial damage and apoptosis. mTOR inhibitor treatment rescues the phenotype in TRPM2-KO mice.\",\n      \"method\": \"TRPM2 KO mice and primary cells, RNA sequencing, Ca2+ flux measurement, AKT-mTOR pathway analysis, mTOR inhibitor rescue, mitochondrial ROS and apoptosis assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with mechanistic pathway rescue, single lab, multiple readouts\",\n      \"pmids\": [\"37649595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPM2 promotes neuroblastoma cell survival through Ca2+-dependent regulation of master transcription factors FOXM1 and E2F1/2. TRPM2 deletion reduces FOXM1 binding to promoters of cell cycle genes (Cyclin B1, CDK1, PLK1, CKS1) and DNA repair genes. Ca2+-impermeable mutant E960D fails to restore viability, establishing Ca2+ permeability as essential. FOXM1 overexpression alone restores viability.\",\n      \"method\": \"CRISPR TRPM2 deletion, RNA sequencing, RT-qPCR, ChIP (FOXM1 promoter binding), Western blot, cell cycle analysis, rescue with WT vs. E960D Ca2+-impermeable mutant, FOXM1 overexpression rescue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR KO, ChIP, mutant rescue, and RNA sequencing in single comprehensive study, multiple orthogonal methods\",\n      \"pmids\": [\"35428820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPM2 is abundantly expressed in lysosomes/autolysosomes of vascular smooth muscle cells and facilitates lysosomal acidification required for autophagic degradation. TRPM2 knockout reduces starvation-induced lysosomal acidification, autophagic flux, and consequent cell death, identifying lysosomal TRPM2 as a regulator of the late (degradation) stage of autophagy.\",\n      \"method\": \"TRPM2 KO mouse aortic smooth muscle cells, lysosomal/autolysosomal fractionation, immunofluorescence co-localization, lysosomal pH measurement, autophagic flux assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization combined with KO functional autophagy readout, single lab\",\n      \"pmids\": [\"33244095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPM2 silencing in TRPM2 stabilizes HIF-1α and Nrf2 proteins via inhibiting their ubiquitination (co-immunoprecipitation), protecting gastric cancer cells from ferroptosis inducers Erastin and RSL3. Activation of HIF-1α impairs ferroptosis after TRPM2 knockdown.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation for HIF-1α/Nrf2 ubiquitination, GSH/GPx/ROS/lipid peroxidation assays, cell viability assays\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of ubiquitination plus functional rescue, single lab\",\n      \"pmids\": [\"36238268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In osteoarthritis chondrocytes, IL-1β upregulates TRPM2 expression via NF-κB-p65 binding to the Trpm2 promoter (validated by ChIP-PCR and ChIP-qPCR). TRPM2-mediated Ca2+ influx causes mitochondrial Ca2+ accumulation → mitochondrial DNA release → cGAS-STING → NF-κB activation, forming a pathological feedforward loop. TRPM2 KO and Ca2+ chelation with BAPTA-AM attenuate OA progression.\",\n      \"method\": \"TRPM2 KO mice (DMM model), ChIP-qPCR for NF-κB-p65 at Trpm2 promoter, siRNA/overexpression in chondrocytes, cGAS-STING pathway analysis, BAPTA-AM Ca2+ chelation in vivo\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of transcriptional regulation, genetic KO, pathway dissection, single lab\",\n      \"pmids\": [\"39505144\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPM2 is a Ca2+-permeable non-selective cation channel with a C-terminal NUDT9-H domain that binds intracellular ADP-ribose (ADPR) to gate the channel; cryo-EM structures reveal that ADPR binding to MHR1/2 and subsequent Ca2+ binding to the transmembrane/TRP-helix region drive concerted conformational changes that open the pore, while oxidative stress activates the channel via PARP-dependent ADPR generation; the channel localizes to the plasma membrane or lysosomal membranes depending on cell type to mediate Ca2+ influx or lysosomal Ca2+/Zn2+ release, respectively, engaging downstream cascades including calcineurin/GSK-3, FOXM1/E2F1 transcription, RAC1/NADPH oxidase, TRPM2–CD36 feedforward signaling, and TRPM2–NMDAR physical coupling, thereby controlling immune cell function, insulin secretion, neuronal survival, synaptic plasticity, and cell death in response to oxidative stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPM2 is a Ca2+-permeable non-selective cation channel that converts oxidative and metabolic stress signals into intracellular Ca2+ (and Zn2+) fluxes governing immune cell function, neuronal survival, and cell death [#0, #1, #2]. The channel is gated by intracellular ADP-ribose binding to its C-terminal NUDT9 homology domain, which also possesses intrinsic ADPR pyrophosphatase activity, while NAD+, cADPR, and NAADP act as co-activators and ATP serves as an endogenous negative regulator [#0, #1, #5]. Oxidative activation by H2O2 proceeds in part through a route separable from direct ADPR gating, and ROS-driven signaling engages PARP-dependent ADPR generation to open the channel [#2, #3, #12, #15]. Cryo-EM structures of zebrafish and human TRPM2 define the gating mechanism: ADPR binds a bi-lobed site in the MHR1/2 domain causing rotation and disruption of intersubunit contacts, and subsequent Ca2+ binding engages the transmembrane helices and TRP helix to open the pore in a concerted fashion [#13, #14]; specific NUDT9H residues (Arg1433, Tyr1349) hydrogen-bond the terminal ribose of ADPR as key gating determinants [#11]. Notably, the enzymatic ADPRase activity is vestigial in vertebrate channels and is dispensable for, and separable from, channel gating [#16]. TRPM2 localizes either to the plasma membrane or to endolysosomal membranes depending on cell type, mediating Ca2+ influx in neutrophils or lysosomal Ca2+/Zn2+ release and lysosomal acidification in dendritic cells, β-cells, and smooth muscle [#6, #9, #26]. Downstream, TRPM2-dependent Ca2+ entry drives calcineurin-mediated GSK-3 dephosphorylation in brain [#10], FOXM1/E2F transcriptional programs supporting tumor cell survival [#25], a RAC1/NADPH oxidase feedforward loop in kidney injury [#7], TRPM2–CD36 feedforward signaling in atherogenic macrophages [#20], and physical coupling to extrasynaptic NMDARs that exacerbates ischemic excitotoxicity [#19]. Channel abundance is set post-translationally by TRIM21-mediated ubiquitination at K1218, which is antagonized by lncTRPM2-AS [#21]. Through these outputs TRPM2 contributes to cell-death pathways including Zn2+-driven β-cell apoptosis, mitochondrial Ca2+/ALOX12-dependent ferroptosis, and cGAS-STING inflammatory loops [#9, #23, #28]. A loss-of-function variant (D543E) failing to dephosphorylate GSK-3 links TRPM2 to bipolar disorder-related phenotypes [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established TRPM2 as a Ca2+-permeable cation channel gated by intracellular ADP-ribose, defining its core molecular identity and a built-in NUDT9 sensor domain.\",\n      \"evidence\": \"Whole-cell/single-channel patch-clamp and biochemical domain identification in HEK-293 cells and native U937 monocytes; parallel Ca2+ imaging in Jurkat/RBL cells\",\n      \"pmids\": [\"11385575\", \"11509734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether NUDT9H enzymatic activity contributes to gating\", \"Endogenous source of activating ADPR not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected TRPM2 to oxidative stress by showing H2O2/ROS activation and redox/NAD+ sensitivity confer susceptibility to cell death, with an activation route separable from direct ADPR gating.\",\n      \"evidence\": \"Patch-clamp, Ca2+ imaging, antisense knockdown in HEK cells; splice variant lacking aa1292-1325 responding to H2O2 but not ADPR\",\n      \"pmids\": [\"11804595\", \"11960981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular intermediary linking H2O2 to channel gating not identified\", \"Relationship between the H2O2 route and endogenous ADPR generation unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified a dominant-negative short isoform (TRPM2-S) that heteromerizes with full-length channel to suppress Ca2+ influx and apoptosis, revealing endogenous regulation of channel output.\",\n      \"evidence\": \"Co-immunoprecipitation, confocal microscopy, Ca2+ flux and cell death assays in HEK293T cells\",\n      \"pmids\": [\"12594222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where TRPM2-S sets channel activity not defined\", \"Stoichiometry of suppression unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Broadened the ligand landscape by showing cADPR and NAADP act as direct co-activators sharing a binding site and synergizing with ADPR in native channels.\",\n      \"evidence\": \"Whole-cell patch-clamp with AMP and 8-Br-cADPR antagonist dissection in Jurkat T cells\",\n      \"pmids\": [\"16585058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, pharmacological inference of shared site\", \"Structural basis of cADPR/NAADP binding not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed cell-type-dependent localization, showing TRPM2 acts as a lysosomal Ca2+ release channel in dendritic cells controlling chemotaxis versus a plasma membrane channel in neutrophils.\",\n      \"evidence\": \"siRNA, TRPM2 KO mice, subcellular fractionation, Ca2+ imaging, chemotaxis and in vivo bacterial trafficking assays\",\n      \"pmids\": [\"21753080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of plasma membrane versus lysosomal targeting unknown\", \"How lysosomal gating ligands are supplied not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated TRPM2 as a driver of organ injury through distinct downstream effectors, including a RAC1/NADPH oxidase feedforward loop in kidney and ROS-coupled Ca2+ entry in acetaminophen hepatotoxicity.\",\n      \"evidence\": \"TRPM2 KO and chimeric mice, RAC1-TRPM2 co-IP, NADPH oxidase assays (kidney); primary hepatocyte patch-clamp, siRNA, KO mice (liver)\",\n      \"pmids\": [\"25295536\", \"24569808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAC1-TRPM2 coupling generalizes beyond proximal tubule unclear\", \"Direct molecular interface of RAC1-TRPM2 not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined Zn2+ (not Ca2+) as the cytotoxic species in β-cell death and showed calcineurin-dependent GSK-3 regulation, linking TRPM2 to diabetes and to a bipolar disorder-associated loss-of-function variant.\",\n      \"evidence\": \"Zn2+/Ca2+ imaging, chelation, TRPM2 KO mice in STZ model (β-cells); KO mice, D543E mutant, calcineurin pharmacology, behavior/EEG (brain)\",\n      \"pmids\": [\"25562606\", \"26311765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source/transport route of lysosomal Zn2+ via TRPM2 not fully resolved\", \"Mechanism connecting calcineurin to behavioral phenotypes incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped key ADPR-gating residues and a CaM-binding temperature sensor in NUDT9H, and established endothelial TRPM2 as a PARP/ADPR-gated mediator of neutrophil transendothelial migration.\",\n      \"evidence\": \"ADPR analogue SAR with Arg1433/Tyr1349 mutagenesis; CaM-binding biophysics + patch-clamp; EC-specific KO, ADPR-insensitive C1008A mutant, PARP silencing, permeability and LPS assays; microglial PARP/NOX/PYK2/MEK-ERK pharmacology\",\n      \"pmids\": [\"28515263\", \"30584900\", \"28790198\", \"28322340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How thermal sensing integrates with ligand gating in vivo unclear\", \"Quantitative contribution of CaM to physiological temperature responses not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural gating mechanism by cryo-EM, showing ADPR binding to MHR1/2 and concerted Ca2+ binding at the transmembrane/TRP-helix region open the pore in both zebrafish and human channels.\",\n      \"evidence\": \"Cryo-EM of apo, ADPR-bound, and ADPR+Ca2+-bound states of zebrafish and human TRPM2\",\n      \"pmids\": [\"30250252\", \"30467180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ADPR-independent H2O2 route not captured\", \"Dynamics of NUDT9H repositioning during gating not time-resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that vertebrate channel gating is uncoupled from NUDT9H catalysis, with vertebrate Nudix activity vestigial and channel/enzyme functions evolutionarily separable.\",\n      \"evidence\": \"Comparative sequence analysis, ADPRase assays of isolated NUDT9H, and patch-clamp/mutagenesis of invertebrate and zebrafish channels\",\n      \"pmids\": [\"30938679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role, if any, of residual human NUDT9H activity unknown\", \"Why pore and enzyme inactivation co-emerged mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended TRPM2 outputs to cell-fate transcriptional and developmental programs and to late-stage autophagy, linking channel Ca2+ flux to FOXM1/E2F survival programs, β-catenin/SP5 in neural progenitors, and lysosomal acidification.\",\n      \"evidence\": \"CRISPR KO, ChIP, Ca2+-impermeable E960D rescue (neuroblastoma); embryo KO/rescue with SP5 (NPCs); KO smooth muscle cells with lysosomal pH and autophagic flux assays\",\n      \"pmids\": [\"35428820\", \"31911949\", \"33244095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling Ca2+ to FOXM1/E2F activity not detailed\", \"How TRPM2 controls lysosomal pH mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-translational and partner-based control of TRPM2, including TRIM21/lncTRPM2-AS-regulated stability at K1218, HIF-1α/Nrf2 stabilization opposing ferroptosis, and physical coupling to extrasynaptic NMDARs driving excitotoxicity.\",\n      \"evidence\": \"RIP/MS, co-IP and ubiquitination assays with K1218 mutant; co-IP of HIF-1α/Nrf2 ubiquitination with viability assays; TRPM2-NMDAR co-IP, surface biotinylation, disruptive peptide in MCAO mice\",\n      \"pmids\": [\"34903714\", \"36238268\", \"35421327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of TRIM21-mediated turnover across tissues unknown\", \"Molecular motif mediating TRPM2-NMDAR association only partly defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified TRPM2–CD36 feedforward signaling in macrophages as a driver of atherosclerosis, expanding TRPM2's role in metabolic-inflammatory disease.\",\n      \"evidence\": \"Global and macrophage-specific conditional KO in ApoE-/- mice, macrophage Ca2+ and CD36 signaling assays, plaque analysis\",\n      \"pmids\": [\"35445217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of TRPM2-CD36 mutual activation not structurally defined\", \"Whether direct physical interaction underlies the feedforward loop unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovered bilirubin as a direct, ADPR/Ca2+-independent TRPM2 agonist and dissected mitochondrial Ca2+/ALOX12 ferroptosis and Ca2+/autophagy outputs in injury, broadening both the agonist repertoire and downstream death pathways.\",\n      \"evidence\": \"Patch-clamp with bilirubin, competitive binding, D1066A knock-in mice in MCAO; KO mice with MCU/ALOX12 ferroptosis dissection (liver IR); KO with AKT-mTOR/autophagy rescue (cisplatin AKI)\",\n      \"pmids\": [\"36921602\", \"37275121\", \"37649595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural overlap of the bilirubin site with other ligand sites not fully mapped\", \"Context determining protective versus detrimental TRPM2 roles in injury unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed transcriptional induction of TRPM2 by NF-κB-p65 and a Ca2+/mitochondrial DNA/cGAS-STING feedforward loop in osteoarthritis, linking channel activity to inflammatory amplification.\",\n      \"evidence\": \"ChIP-qPCR at Trpm2 promoter, TRPM2 KO DMM mice, chondrocyte siRNA/overexpression, cGAS-STING pathway analysis, BAPTA-AM rescue\",\n      \"pmids\": [\"39505144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; generality of the cGAS-STING loop to other tissues untested\", \"How mitochondrial Ca2+ overload triggers mtDNA release mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of the ADPR-independent oxidative/H2O2 activation route and the determinants directing TRPM2 to plasma membrane versus lysosomal compartments remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure captures the H2O2-activated state\", \"Trafficking signals controlling subcellular targeting not identified\", \"Mechanism converting context-specific signals into protective versus cytotoxic Ca2+/Zn2+ output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 6, 9, 13, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 22]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6, 9, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 9, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 9, 23, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 12, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRPM2 (TRPM2-S isoform)\", \"RAC1\", \"NMDAR\", \"CD36\", \"TRIM21\", \"calmodulin\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}