| 2001 |
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. |
Whole-cell and single-channel patch-clamp electrophysiology; biochemical identification of NUDT9 homology domain; heterologous expression in HEK-293 cells |
Nature |
High |
11385575
|
| 2001 |
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. |
Whole-cell patch-clamp, Ca2+ imaging, heterologous expression |
Science (New York, N.Y.) |
High |
11509734
|
| 2002 |
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. |
Whole-cell patch-clamp, Ca2+ imaging, antisense oligonucleotide knockdown, heterologous expression in HEK cells |
Molecular cell |
High |
11804595
|
| 2002 |
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. |
Whole-cell patch-clamp, Ca2+ imaging, splice variant cloning from neutrophil granulocytes, heterologous expression |
The Journal of biological chemistry |
High |
11960981
|
| 2003 |
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. |
Co-immunoprecipitation, confocal microscopy, Ca2+ flux assays, cell death assays, heterologous expression in HEK293T cells |
The Journal of biological chemistry |
High |
12594222
|
| 2006 |
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. |
Whole-cell patch-clamp in Jurkat T cells, pharmacological dissection with AMP and 8-Br-cADPR antagonists |
FASEB journal |
Medium |
16585058
|
| 2011 |
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. |
siRNA knockdown, TRPM2 knockout mice, confocal microscopy subcellular fractionation, Ca2+ imaging, chemotaxis assays, in vivo bacterial infection model |
FASEB journal |
High |
21753080
|
| 2014 |
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. |
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 |
The Journal of clinical investigation |
High |
25295536
|
| 2014 |
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. |
Whole-cell patch-clamp in primary hepatocytes, siRNA knockdown, TRPM2 KO mice, liver enzyme assays and histology |
Proceedings of the National Academy of Sciences of the United States of America |
High |
24569808
|
| 2015 |
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. |
Fluorescent Zn2+ and Ca2+ imaging, Zn2+ chelation, TRPM2 KO mice (STZ model), patch-clamp, lysosome TRPM2 localization |
The Biochemical journal |
High |
25562606
|
| 2015 |
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. |
TRPM2 KO mice, D543E mutant overexpression, biochemical GSK-3 phosphorylation assays, calcineurin inhibitor pharmacology, behavioral tests, EEG |
The Journal of neuroscience |
High |
26311765
|
| 2017 |
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. |
Synthetic ADPR analogue library, whole-cell patch-clamp, site-directed mutagenesis of NUDT9H domain, structure-activity relationship analysis |
The Biochemical journal |
High |
28515263
|
| 2017 |
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. |
Conditional EC-specific TRPM2 knockout mice, ADPR-insensitive mutant overexpression, PARP silencing, Ca2+ imaging, permeability assays, LPS challenge in vivo |
Circulation research |
High |
28790198
|
| 2018 |
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. |
Cryo-electron microscopy structural determination of apo and ligand-bound states |
Nature |
High |
30250252
|
| 2018 |
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. |
Cryo-electron microscopy of three distinct states of human TRPM2 |
Science (New York, N.Y.) |
High |
30467180
|
| 2017 |
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. |
TRPM2 KO cells, PARP inhibitors (PJ34, DPQ), NOX inhibitors, PKC inhibitor, PYK2 inhibitor, MEK/ERK inhibitor, Ca2+ imaging, cell viability assays |
Scientific reports |
Medium |
28322340
|
| 2019 |
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. |
Comparative sequence analysis, ADPRase activity assays of isolated NUDT9H domains, patch-clamp electrophysiology of nvTRPM2 and drTRPM2 channels with mutagenesis |
eLife |
High |
30938679
|
| 2018 |
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. |
Biophysical characterization of CaM binding (ITC, NMR, crystallography), patch-clamp electrophysiology of full-length TRPM2 |
Biochimica et biophysica acta. Molecular cell research |
Medium |
30584900
|
| 2020 |
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. |
TRPM2 knockdown and knockout in mouse embryos, neural stem cell culture, immunofluorescence, Western blot, rescue experiments with TRPM2 and SP5 overexpression |
Science advances |
Medium |
31911949
|
| 2021 |
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. |
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 |
Neuron |
High |
35421327
|
| 2022 |
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. |
Global and macrophage-specific conditional TRPM2 KO in ApoE-/- mice, cultured macrophage Ca2+ measurements, CD36 signaling assays, atherosclerotic plaque analysis |
Nature cardiovascular research |
High |
35445217
|
| 2021 |
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. |
RNA immunoprecipitation, mass spectrometry, co-IP of TRPM2-TRIM21, ubiquitination assays with K1218 mutation analysis, Ca2+ and ROS measurements, siRNA knockdown |
Cell death & disease |
Medium |
34903714
|
| 2023 |
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. |
Patch-clamp electrophysiology with bilirubin and metabolites, competitive binding assays, TRPM2 KO mice, TRPM2-D1066A knock-in mice, ischemic stroke (MCAO) model in vivo |
Neuron |
High |
36921602
|
| 2023 |
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. |
TRPM2 KO mice (hepatic IR model), mitochondrial Ca2+ imaging, ALOX12 expression analysis, ferroptosis markers, RSL3 treatment, MCU inhibitor, TRPM2 inhibitor |
Research (Washington, D.C.) |
Medium |
37275121
|
| 2023 |
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. |
TRPM2 KO mice and primary cells, RNA sequencing, Ca2+ flux measurement, AKT-mTOR pathway analysis, mTOR inhibitor rescue, mitochondrial ROS and apoptosis assays |
Theranostics |
Medium |
37649595
|
| 2022 |
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. |
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 |
Scientific reports |
High |
35428820
|
| 2020 |
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. |
TRPM2 KO mouse aortic smooth muscle cells, lysosomal/autolysosomal fractionation, immunofluorescence co-localization, lysosomal pH measurement, autophagic flux assays |
Scientific reports |
Medium |
33244095
|
| 2021 |
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. |
siRNA knockdown, co-immunoprecipitation for HIF-1α/Nrf2 ubiquitination, GSH/GPx/ROS/lipid peroxidation assays, cell viability assays |
Cytotechnology |
Medium |
36238268
|
| 2024 |
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. |
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 of advanced research |
Medium |
39505144
|