Affinage

TRPM4

Transient receptor potential cation channel subfamily M member 4 · UniProt Q8TD43

Length
1214 aa
Mass
134.3 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM4 is a Ca2+-activated, voltage-modulated, monovalent-selective (Na+/K+) non-selective cation channel that assembles as a homotetramer and converts intracellular Ca2+ signals into membrane depolarization across diverse excitable and non-excitable cell types (PMID:26785754, PMID:16806463). Cryo-EM structures define a three-tiered architecture in which an N-terminal nucleotide-binding domain binds inhibitory ATP, C-terminal coiled-coil and MHR regions mediate tetrameric assembly, and the S1-S4/TRP gating module houses Ca2+- and PtdIns(4,5)P2-binding sites controlling an upper selectivity-filter gate and a lower cytoplasmic gate, with a filter glutamine (Gln973) dictating monovalent selectivity (PMID:29211714, PMID:29211723, PMID:29463718). Gating is tuned by phospholipid and kinase inputs: PIP2 binding to C-terminal PH-domain basic residues and a proximal N-terminal region counteracts desensitization and raises Ca2+ sensitivity, PKCδ phosphorylation increases Ca2+ sensitivity and maintains surface expression, and NO/cGMP/PKG signaling inhibits the channel via IRAG-dependent suppression of IP3R Ca2+ release (PMID:16424899, PMID:26071843, PMID:17293488, PMID:21406958, PMID:34734188). Small-molecule inhibitors bind a pocket between the S3, S4, and TRP helices and the S4-S5 linker (PMID:39828793), and anterograde trafficking to the plasma membrane depends on EB1/EB2 microtubule-plus-end proteins (PMID:31112396). Physiologically, TRPM4-mediated depolarization modulates voltage-gated Ca2+ entry and electrical activity in cerebral arterial smooth muscle myogenic tone, cardiac myocytes, pancreatic beta- and acinar cells, taste receptor cells, and central neurons (PMID:17293488, PMID:24226423, PMID:16806463, PMID:34329682, PMID:29311301, PMID:32414784), and it controls Ca2+-dependent processes including insulin and mucin secretion, mast cell and macrophage function, and T cell NFAT signaling (PMID:16806463, PMID:30482841, PMID:19046767, PMID:22933633, PMID:20656926). TRPM4 co-assembles with SUR1 to form NC(Ca-ATP) channels with doubled calmodulin and Ca2+ sensitivity, and further with AQP4 into a tripartite complex that drives oncotic astrocyte swelling and brain edema after injury, with Na+ influx coupling through reverse-mode NCX1 to trigger AQP4 translocation (PMID:23255597, PMID:28906027, PMID:37279286). TRPM4 physically couples to NMDA receptors to mediate excitotoxic neuronal death independently of NMDAR Ca2+ signals (PMID:33033186), and sustained Na+ overload through TRPM4 executes oncotic necrosis exploited in necrosis-inducing cancer therapy (PMID:19169264, PMID:37522838, PMID:39915626). Gain-of-function S6 mutations cause autosomal dominant progressive symmetric erythrokeratodermia, and gain-of-expression variants cause progressive familial heart block, while TRPM4 contributes to triggered cardiac arrhythmias and pressure-overload hypertrophy (PMID:30528822, PMID:26820365, PMID:35822895, PMID:34190686).

Mechanistic history

Synthesis pass · year-by-year structured walk · 42 steps
  1. 2006 High

    Established how a lipid signal sets TRPM4 sensitivity, explaining why receptor-driven PIP2 hydrolysis dampens the channel and resolving the basis of Ca2+ desensitization.

    Evidence Inside-out and whole-cell patch-clamp with PH-domain mutagenesis and pharmacological/M1-receptor PIP2 depletion

    PMID:16424899

    Open questions at the time
    • Did not resolve the structural location of the PIP2 site
    • Functional interplay between PIP2 and ATP regulation not addressed
  2. 2006 High

    Defined a core physiological role: TRPM4 generates Ca2+-triggered depolarizing current that gates electrical activity and hormone secretion in beta-cells.

    Evidence Patch-clamp, dominant-negative TRPM4, capacitance and insulin secretion assays, vesicle imaging in INS-1 cells

    PMID:16806463

    Open questions at the time
    • Dominant-negative effects not validated against genetic knockout
    • Mechanism of TRPM4 vesicular recruitment unresolved
  3. 2007 High

    Linked TRPM4 to vascular tone by showing PKC phosphorylation potentiates the channel to drive myogenic vasoconstriction.

    Evidence Patch-clamp, antisense knockdown, PMA stimulation, and myogenic tone measurement in cerebral arteries

    PMID:17293488

    Open questions at the time
    • Specific phosphorylation residues not mapped
    • PKC isoform identity not yet pinned down in this study
  4. 2009 High

    Identified TRPM4 as the effector of oncotic capillary death after CNS injury, establishing it as a therapeutic target for secondary hemorrhage.

    Evidence Spinal cord injury models with antisense and Trpm4-/- mice plus in vitro swelling assays

    PMID:19169264

    Open questions at the time
    • Did not define the molecular partners enabling water flux
    • Trigger for de novo upregulation not identified here
  5. 2011 Medium

    Showed PKCδ maintains TRPM4 at the plasma membrane, separating a trafficking control from gating regulation.

    Evidence siRNA and pharmacological PKCδ inhibition with immunolabeling and perforated-patch recording in cerebral artery SMCs

    PMID:21406958

    Open questions at the time
    • Single lab, single cell type
    • Direct phosphorylation of TRPM4 by PKCδ not demonstrated
  6. 2012 Medium

    Connected TRPM4 to proliferative β-catenin signaling, indicating a non-electrical role in cell growth.

    Evidence siRNA knockdown, overexpression, β-catenin phosphorylation Western blot, Tcf/Lef reporter in HeLa cells

    PMID:20625999

    Open questions at the time
    • Mechanism linking channel activity to GSK-3β not defined
    • Single cell line
  7. 2012 High

    Revealed cell-type-specific immune roles, with TRPM4 required for macrophage Ca2+ mobilization and host defense in sepsis.

    Evidence Trpm4-/- mice in cecal ligation/puncture with Ca2+ imaging, AKT analysis, and phagocytosis assays

    PMID:22933633

    Open questions at the time
    • Mechanism coupling TRPM4 to AKT not resolved
    • Why neutrophils are unaffected not explained
  8. 2012 High

    Defined the SUR1-TRPM4 heteromeric channel and showed SUR1 doubles calmodulin and Ca2+ sensitivity, explaining injury-induced NC(Ca-ATP) currents.

    Evidence FRET, reciprocal co-IP, patch-clamp in co-transfected cells, calmodulin binding assay, spinal cord injury model

    PMID:23255597

    Open questions at the time
    • Stoichiometry of the SUR1-TRPM4 assembly not defined
    • Structural basis of sensitivity enhancement unknown
  9. 2013 High

    Established a cardiac role: TRPM4 shapes ventricular repolarization and β-adrenergic inotropy via Ca2+-induced Ca2+ release.

    Evidence Trpm4-/- mice with patch-clamp, contractility, and in vivo pressure-volume analysis

    PMID:24226423

    Open questions at the time
    • Subcellular localization in myocytes not mapped
    • Coupling to specific Ca2+ release sites not defined
  10. 2010 Medium

    Showed TRPM4 differentially sets Ca2+ influx and NFATc1 signaling between Th1 and Th2 cells, tuning adaptive immune output.

    Evidence siRNA knockdown, Ca2+ imaging, NFATc1 nuclear localization, cytokine and motility assays

    PMID:20656926

    Open questions at the time
    • Mechanism of opposite effects in Th1 vs Th2 unexplained
    • siRNA-only, single lab
  11. 2014 Medium

    Mapped a single N-glycosylation site (Asn992) and showed it regulates function rather than surface trafficking.

    Evidence N992Q mutagenesis, tunicamycin, Western blot, patch-clamp, surface biotinylation

    PMID:24605085

    Open questions at the time
    • Mutation and drug results were partly discordant
    • Functional consequence mechanistically unresolved
  12. 2015 Medium

    Localized a proximal N-terminal phosphoinositide-binding region (E733-W772, R755/R767), complementing the C-terminal PIP2 determinants.

    Evidence Biophysical binding assays, molecular modeling, mutagenesis

    PMID:26071843

    Open questions at the time
    • Limited functional electrophysiological validation
    • Selectivity between PIP2 and PIP3 not fully resolved
  13. 2015 Medium

    Demonstrated native TRPM4 currents in primary cilia and a structural role in cilium length, extending the channel to ciliary signaling.

    Evidence Direct patch-clamp from excised cilia, shRNA knockdown, pharmacology in mIMCD-3 cells

    PMID:26290373

    Open questions at the time
    • Mechanism linking TRPM4 to cilium length unknown
    • Single lab
  14. 2016 High

    Confirmed TRPM4 forms a functional homotetramer sufficient for channel activity by reconstitution.

    Evidence Purification, crosslinking, native PAGE, MALLS, EM, and single-channel recording of proteoliposomes

    PMID:26785754

    Open questions at the time
    • Did not resolve atomic architecture
    • Regulatory subunit requirements in vivo not addressed
  15. 2016 High

    Showed SUR1-TRPM4 paradoxically controls NFAT-driven NOS2 transcription in activated microglia through Ca2+-dependent CaMKII/calcineurin signaling.

    Evidence ChIP, co-IP, patch-clamp, Ca2+ imaging, Trpm4-/- and Abcc8-/- mice with LPS activation

    PMID:27246103

    Open questions at the time
    • Mechanism of the paradoxical Ca2+/NFAT relationship incompletely defined
  16. 2016 Medium

    Extended TRPM4 cancer signaling to a Ca2+/calmodulin-EGFR-Akt-GSK-3β-β-catenin axis controlling prostate cancer proliferation.

    Evidence siRNA, overexpression, phospho-Western blots, Tcf/Lef reporter in PC3 cells

    PMID:28614631

    Open questions at the time
    • Direct linkage of channel ion flux to Akt unproven
    • Single lab
  17. 2016 Medium

    Identified the first cardiac gain-of-expression mechanism for a disease variant (p.I376T) in progressive familial heart block type I.

    Evidence Whole-cell patch-clamp, Western blot, surface expression in HEK293

    PMID:26820365

    Open questions at the time
    • In vivo conduction phenotype not modeled
    • Heterologous-only system
  18. 2016 Medium

    Characterized U73122 as a covalent, PLC-independent TRPM4 agonist selective within the TRPM family, refining pharmacology.

    Evidence Whole-cell patch-clamp across CHO, Jurkat, HEK293T, and recombinant TRPM4 vs TRPM5

    PMID:27328745

    Open questions at the time
    • Covalent modification site not identified
    • Single lab
  19. 2017 High

    Resolved TRPM4 architecture and the structural basis of ATP inhibition, monovalent selectivity, and assembly via cryo-EM.

    Evidence Cryo-EM of mouse TRPM4 ±ATP and human TRPM4 with Ca2+/decavanadate, with functional validation

    PMID:29211714 PMID:29211723

    Open questions at the time
    • Open/conducting state not captured in these structures
    • PIP2-bound state not resolved
  20. 2017 High

    Defined the tripartite SUR1-TRPM4-AQP4 complex as the molecular machine driving high-capacity water flux and astrocyte swelling.

    Evidence Co-IP, FRET, calcein swelling assay in COS-7/astrocytes, in vivo cold-injury model with genetic inactivation

    PMID:28906027

    Open questions at the time
    • Stoichiometry of the tripartite complex not determined
    • Coupling mechanism between ion and water channels unresolved at this stage
  21. 2018 High

    Captured the closed Na+-bound state, defining upper/lower gates, lipid sites, and intramolecular gating contacts.

    Evidence Cryo-EM at 3.7 Å with detailed pore, glycosylation, and lipid-site analysis

    PMID:29463718

    Open questions at the time
    • Conformational transitions to the open state not visualized
  22. 2018 High

    Provided the first structure-informed disease mechanism: S6 activation-gate gain-of-function mutations cause erythrokeratodermia by raising basal channel activity and keratinocyte proliferation.

    Evidence Genetic sequencing, cryo-EM-informed analysis, mutant patch-clamp, keratinocyte proliferation assays

    PMID:30528822

    Open questions at the time
    • Link between depolarization and proliferation not fully mechanistic
    • In vivo skin phenotype not modeled
  23. 2018 High

    Defined TRPM4 as a downstream depolarizing element required for bitter/sweet/umami taste transduction alongside TRPM5.

    Evidence Single, double KO mice with Ca2+ imaging and behavioral taste assays

    PMID:29311301

    Open questions at the time
    • Relative contribution of TRPM4 vs TRPM5 per cell type not separated
  24. 2018 Medium

    Expanded TRPM4 function to regulated exocytosis by showing it cooperates with NCX to drive mucin secretion in epithelia.

    Evidence Pharmacological TRPM4/NCX inhibition with mucin secretion assays in multiple epithelial cell lines

    PMID:30482841

    Open questions at the time
    • No genetic confirmation
    • Physical TRPM4-NCX interaction not shown
  25. 2018 Medium

    Localized neuronal TRPM4 to soma/proximal dendrites with a resting-active current, and to inspiratory pattern generation, defining a role in setting excitability.

    Evidence Immunofluorescence and perforated-patch with local 9-phenanthrol perfusion; RT-PCR and pharmacology in preBötzinger neurons

    PMID:29435486 PMID:29440991

    Open questions at the time
    • 9-phenanthrol selectivity is a caveat
    • No genetic loss-of-function in these neuronal studies
  26. 2018 Medium

    Linked TRPM4 to prostate cancer EMT and invasion via Snail1, defining a metastasis-relevant role.

    Evidence shRNA knockdown, overexpression, EMT marker Westerns, migration/invasion assays

    PMID:30343491

    Open questions at the time
    • Connection between ion flux and Snail1 regulation unresolved
    • Single lab
  27. 2019 Medium

    Identified EB1/EB2 as the trafficking partners directing TRPM4 anterograde transport that supports focal adhesion turnover and invasion.

    Evidence Co-IP, motif mutagenesis, localization imaging, dominant-negative EB fragment, focal adhesion and invasion assays

    PMID:31112396

    Open questions at the time
    • EB-binding motif not structurally mapped
    • Single lab
  28. 2019 Medium

    Defined a tPA/plasmin/PAR1/TRPC3 pathway that opens SUR1-TRPM4 to drive phasic MMP-9 secretion from inflamed brain endothelium.

    Evidence Patch-clamp, ELISA/zymography for MMP-9, genetic and pharmacological inhibition, Ca2+ imaging

    PMID:29617457

    Open questions at the time
    • Direct physical coupling to TRPC3 not shown
    • Single lab
  29. 2020 High

    Revealed a physical TRPM4-NMDA receptor complex that mediates excitotoxic death independently of NMDAR Ca2+ flux, defining a druggable interface.

    Evidence Co-IP, structure-based drug screening, Ca2+ imaging, and neuronal loss in stroke and retinal degeneration models

    PMID:33033186

    Open questions at the time
    • Atomic structure of the interface not resolved
    • How the complex executes death without altering Ca2+ not fully defined
  30. 2020 Medium

    Showed TRPM4 drives plateau potentials and oscillatory firing in thalamic reticular neurons via T-type Ca2+ channel input.

    Evidence Thalamic slice electrophysiology with TRPM4 and T-type channel pharmacology

    PMID:32414784

    Open questions at the time
    • Pharmacology-only, no genetic confirmation
  31. 2020 Medium

    Linked TRPM4 upregulation to cardiac fibrogenesis by showing TGFβ1 increases fibroblast TRPM4 currents in heart failure.

    Evidence Patch-clamp of primary human fibroblasts, Western blot, TGFβ1 stimulation

    PMID:33594499

    Open questions at the time
    • Functional consequence for fibrosis not directly tested
    • Single lab
  32. 2021 High

    Resolved the NO/cGMP/PKG vasodilation mechanism as IRAG-mediated suppression of IP3R Ca2+ release that withdraws Ca2+ activation of TRPM4.

    Evidence Electrophysiology, Ca2+ imaging, sGC/PKG inhibitors, IRAG siRNA, superresolution microscopy, myogenic response

    PMID:34734188

    Open questions at the time
    • Direct PKG phosphorylation of TRPM4 itself not demonstrated
  33. 2021 High

    Established TRPM4 as a negative-feedback regulator of Ca2+ entry in pancreatic acinar cells through depolarization.

    Evidence Trpm4-/- mice, whole-cell/perforated patch, CBA inhibition, Ca2+ imaging with cerulein

    PMID:34329682

    Open questions at the time
    • Relevance to pancreatitis pathophysiology not established in this study
  34. 2021 High

    Identified TRPM4 as a mechanosensory signaling component driving pressure-overload left ventricular hypertrophy.

    Evidence Cardiomyocyte-specific conditional Trpm4 KO with transverse aortic constriction

    PMID:34190686

    Open questions at the time
    • Direct mechanosensing mechanism of TRPM4 not defined
    • Downstream hypertrophic signaling not mapped
  35. 2022 High

    Established TRPM4 as a contributor to triggered ventricular arrhythmias via a Ca2+ overload-induced background current.

    Evidence Trpm4-/- mice, compound screening (meclofenamate), in vitro electrophysiology, in vivo ECG in proarrhythmic models

    PMID:35822895

    Open questions at the time
    • Meclofenamate selectivity caveat
    • Subcellular Ca2+ source not pinpointed
  36. 2022 Medium

    Defined transcriptional control of TRPM4 by p53/p63γ, linking tumor-suppressor loss to elevated TRPM4 currents and altered cell cycle.

    Evidence CRISPR KO, p53/p63γ overexpression, promoter-reporter, patch-clamp, Ca2+ imaging, cell cycle analysis in colorectal cells

    PMID:35500522

    Open questions at the time
    • Direct p53 binding to TRPM4 promoter regions not fully mapped
    • Single lab
  37. 2022 Medium

    Showed TRPM4 can suppress migration via a Ca2+/calpain/FAK axis, indicating context-dependent pro- and anti-invasive roles across cancers.

    Evidence Overexpression, calpain inhibition rescue, Western blots, migration assays, in vivo tumor model in colorectal cells

    PMID:36147460

    Open questions at the time
    • Reconciliation with pro-invasive prostate findings not addressed
    • Single lab
  38. 2023 High

    Defined the downstream Na+/NCX1/calmodulin/AQP4 cascade by which SUR1-TRPM4 in astrocyte endfeet causes post-ischemic brain swelling.

    Evidence Mouse ischemic stroke, SUR1-TRPM4 and NCX1 inhibition, astrocyte-specific deletion, Ca2+ imaging, AQP4 surface assays

    PMID:37279286

    Open questions at the time
    • Whether NCX1 physically associates with the complex not shown
  39. 2023 Medium

    Demonstrated functional coupling of TRPM4 to mechanosensitive Piezo1 and to TRPV4, positioning it as a shared depolarizing effector for upstream Ca2+ channels.

    Evidence siRNA, pharmacology, voltage/Ca2+ imaging in HL-1 cells and heterologous TRPV4/TRPM4 co-expression

    PMID:35432302 PMID:38098265

    Open questions at the time
    • Direct physical interaction with Piezo1/TRPV4 not established
    • Cell-line models
  40. 2023 High

    Identified TRPM4-mediated Na+ influx and swelling as essential for ErSO-induced necrotic cancer cell death through sustained UPR hyperactivation.

    Evidence Genome-wide CRISPR screen, TRPM4 KO cells and tumor models, volume and ATP-depletion assays

    PMID:37522838

    Open questions at the time
    • Mechanism connecting Na+/swelling to UPR amplification not fully defined
  41. 2023 High

    Established that age-dependent PIP2 depletion via TGF-β-driven PI3K hyperactivity impairs TRPM4 and vascular myogenic response in a Gould syndrome model.

    Evidence Patch-clamp of native SMCs from Col4a1 mutant mice, PIP2 dialysis, PI3K and TGF-β inhibitors, myogenic measurements

    PMID:36693102

    Open questions at the time
    • Generality beyond Col4a1 mutant model not established
  42. 2025 High

    Mapped the inhibitor-binding pocket (S3/S4/TRP helices and S4-S5 linker) and defined species-specific NECSO pharmacology, enabling rational modulation of necrotic cell death.

    Evidence Cryo-EM in nanodiscs ±NBA/IBA with patch-clamp validation; domain swapping and docking for NC1, with KO and GoF-mutant cell death assays

    PMID:39828793 PMID:39915626

    Open questions at the time
    • Open-state structure with bound activators not resolved
    • Therapeutic window for NECSO-based therapy not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRPM4's identical depolarizing activity produces opposing pro- vs anti-proliferative/invasive outcomes across tissues, and how ion flux is coupled to non-electrical signaling (β-catenin, Akt, calpain/FAK, UPR), remains unresolved.
  • No unifying mechanism linking depolarization to the divergent transcriptional/proliferative phenotypes
  • Open/conducting structural state and activator-bound states not yet captured
  • Physical versus functional nature of several reported channel couplings (Piezo1, TRPV4, NCX, TRPC3) not always distinguished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 3 GO:0005198 structural molecule activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005929 cilium 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-397014 Muscle contraction 3
Partners
ABCC8 (SUR1)AQP4GRIN1/NMDA RECEPTORMAPRE1 (EB1)MAPRE2 (EB2)NCX1PRKCD (PKCΔ)TRPV4
Complex memberships
SUR1-TRPM4 (NC(Ca-ATP)) channelSUR1-TRPM4-AQP4 tripartite channel complexTRPM4 homotetramerTRPM4-NMDA receptor complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PIP2 counteracts Ca2+ desensitization and rundown of TRPM4 currents, shifts voltage dependence toward negative potentials, and increases Ca2+ sensitivity 100-fold. Neutralization of basic residues in the C-terminal pleckstrin homology (PH) domain accelerated desensitization and attenuated PIP2 effects. PLC-mediated PIP2 breakdown inhibits TRPM4 activity. Inside-out and whole-cell patch-clamp; site-directed mutagenesis of PH domain residues; pharmacological PIP2 depletion; M1 muscarinic receptor activation The EMBO journal High 16424899
2017 Cryo-EM structure of mouse TRPM4 (with and without ATP) reveals a three-tiered architecture: N-terminal nucleotide-binding domain (NBD) and C-terminal coiled-coil participate in tetrameric assembly; ATP binds at the NBD and inhibits channel activity; filter residue Gln973 is essential for monovalent selectivity; S1-S4 domain and post-S6 TRP domain form the central gating apparatus housing Ca2+- and PtdIns(4,5)P2-binding sites. Electron cryo-microscopy (cryo-EM) structure determination with and without ATP Nature High 29211714
2017 Cryo-EM structure of human TRPM4 bound to Ca2+ and decavanadate reveals four C-terminal cytosolic domains forming an umbrella-like structure with coiled-coil pole and helical ribs spanning MHR regions; two decavanadate-binding sites identified (C-terminal domain and intersubunit MHR interface); a selectivity-filter glutamine is an important determinant of monovalent selectivity. Electron cryo-microscopy (cryo-EM) structure determination Nature High 29211723
2018 Cryo-EM structure of full-length human TRPM4 in a closed Na+-bound apo state identifies an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain; intramolecular interactions between TRP domain and S4-S5 linker, N-terminal domain, and N/C termini; N-linked glycosylation at one extracellular site; pore-loop disulfide bond; 24 lipid binding sites; five partially hydrated Na+ ions in the conduction pore. Electron cryo-microscopy (cryo-EM) at 3.7 Å resolution Proceedings of the National Academy of Sciences of the United States of America High 29463718
2025 Cryo-EM structures of full-length human TRPM4 in nanodiscs with and without inhibitors NBA and IBA reveal that small molecule inhibitors bind in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker. Patch-clamp experiments validated this binding site functionally. Cryo-EM structure determination in native lipid nanodiscs; patch-clamp electrophysiology Nature communications High 39828793
2012 SUR1 and TRPM4 co-assemble to form SUR1-TRPM4 heteromeric channels (NC(Ca-ATP) channels). Co-expression yielded channels with biophysical properties of TRPM4 and pharmacological properties of SUR1. Co-assembly with SUR1 doubled TRPM4 affinity for calmodulin and doubled its sensitivity to intracellular calcium. SUR1-TRPM4 heteromers appear de novo after spinal cord injury. FRET; co-immunoprecipitation; whole-cell patch-clamp in co-transfected cells; calmodulin binding assay; spinal cord injury rat model The Journal of biological chemistry High 23255597
2017 AQP4 physically co-assembles with SUR1-TRPM4 to form a heteromultimeric water/ion channel complex (SUR1-TRPM4-AQP4). The full tripartite complex is required for fast, high-capacity transmembrane water transport driving cell swelling. In a brain edema model, astrocytes newly upregulate SUR1-TRPM4, which co-associates with AQP4, and genetic inactivation of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling. Co-immunoprecipitation; FRET; calcein fluorescence cell-swelling assay in COS-7 cells and primary astrocytes; cold-injury mouse model with diolistic labeling Glia High 28906027
2007 PKC activity enhances TRPM4 activation by increasing its Ca2+ sensitivity in cerebral arterial smooth muscle cells. PKCδ-dependent phosphorylation promotes pressure-induced smooth muscle depolarization and myogenic vasoconstriction. TRPM4 antisense knockdown in cerebral arteries reduced TRPM4-like currents and diminished PKC-induced depolarization and vasoconstriction. Patch-clamp electrophysiology; antisense oligonucleotide knockdown; phorbol ester (PMA) stimulation; myogenic tone measurement in isolated cerebral arteries American journal of physiology. Heart and circulatory physiology High 17293488
2020 TRPM4 physically couples to NMDA receptors via intracellular domains located in the near-membrane portions of the receptors. This interaction is required for NMDAR-mediated excitotoxicity; disrupting the NMDAR/TRPM4 complex eliminates toxicity without affecting NMDAR-induced Ca2+ signals. Structure-based computational drug screening using the TRPM4-NMDAR interaction interface identified small molecules that disrupt this complex and reduce neuronal loss in mouse models of stroke and retinal degeneration. Co-immunoprecipitation; structure-based computational drug screening; neuronal loss assays in mouse stroke and retinal degeneration models; Ca2+ imaging Science (New York, N.Y.) High 33033186
2011 PKCδ activity maintains TRPM4 channel protein at the plasma membrane of cerebral artery smooth muscle cells. siRNA-mediated downregulation or pharmacological inhibition of PKCδ causes TRPM4 to move from plasma membrane into the cytosol and diminishes TRPM4-dependent currents. siRNA knockdown of PKCδ; pharmacological PKCδ inhibition (rottlerin); immunolabeling; perforated-patch electrophysiology Channels (Austin, Tex.) Medium 21406958
2006 TRPM4 controls membrane potential and electrical activity in insulin-secreting INS-1 beta-cells by generating large depolarizing currents in response to increased intracellular Ca2+. A dominant-negative TRPM4 construct significantly decreased insulin secretion in response to glucose and vasopressin. TRPM4-containing vesicles are recruited to the plasma membrane during Ca2+-dependent exocytosis. Patch-clamp electrophysiology; dominant-negative TRPM4 construct; insulin secretion assay; capacitance measurements; FM1-43 dye; confocal imaging Cell calcium High 16806463
2008 TRPM4 controls migration of bone marrow-derived mast cells (BMMCs). TRPM4 knockout BMMCs fail to migrate in response to DNP-HSA or SCF. TRPM4 regulates Ca2+-dependent F-actin rearrangements required for cell migration. TRPM4 knockout mice; migration assays; cytochalasin B inhibition; phalloidin immunofluorescence for F-actin Cell calcium Medium 19046767
2009 De novo upregulation of TRPM4 in spinal cord capillaries renders cells susceptible to oncotic swelling and death upon ATP depletion. In vivo, Trpm4 antisense treatment or Trpm4-/- mice prevented secondary hemorrhage, capillary fragmentation, and reduced lesion volume after spinal cord injury. Rodent spinal cord injury models; antisense knockdown in rats; Trpm4-/- mice; cell swelling assays in COS-7 cells expressing TRPM4; histology Nature medicine High 19169264
2010 TRPM4 is expressed at higher levels in Th2 versus Th1 cells and differentially regulates Ca2+ influx and NFATc1 nuclear localization. Inhibition of TRPM4 expression increased Ca2+ influx in Th2 cells and decreased it in Th1 cells, altering cytokine production and T cell motility. siRNA knockdown; Ca2+ imaging; nuclear localization assays; cytokine measurements; motility assays Journal of immunology (Baltimore, Md. : 1950) Medium 20656926
2012 TRPM4 deficiency or pharmacological inhibition reduces axonal and neuronal degeneration in EAE without altering immune function. TRPM4 mediates Na+ influx and oncotic cell swelling upon excitotoxic stimulation in neurons. Trpm4-/- mice; EAE model; glibenclamide pharmacological inhibition; electrophysiological recordings of ion influx; cell swelling measurements in vitro Nature medicine High 23160238
2014 N-linked glycosylation of TRPM4 occurs at a unique residue Asn992. Abolishing glycosylation by N992Q mutation or tunicamycin treatment differentially affects current density but does not alter channel trafficking to the plasma membrane, indicating glycosylation mainly regulates TRPM4 function rather than surface expression. Site-directed mutagenesis (N992Q); tunicamycin treatment; Western blot; patch-clamp electrophysiology; surface biotinylation Frontiers in cellular neuroscience Medium 24605085
2015 PIP2 and PIP3 interact with the E733-W772 proximal N-terminal region of TRPM4. Residues R755 and R767 are important for PIP2/PIP3 binding; their mutation caused partial loss of binding specificity. Biophysical binding assays; molecular modeling; mutagenesis of R755 and R767 Biophysical chemistry Medium 26071843
2019 TRPM4 interacts with end-binding (EB) proteins EB1 and EB2 via a putative motif in TRPM4. Mutations abolishing this interaction reduce mature plasma membrane TRPM4 and result in ER-associated distribution. EB1/EB2 are required for TRPM4 anterograde trafficking and functional activity, which in turn regulate focal adhesion disassembly and cell invasion. Co-immunoprecipitation; mutagenesis of EB binding motif; subcellular localization imaging; dominant-negative EB binding fragment; focal adhesion assays; invasion assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 31112396
2013 TRPM4 is activated by Ca2+-induced Ca2+ release in mouse ventricular myocytes and its loss in Trpm4-/- mice leads to increased β-adrenergic inotropic response, shortened action potential duration at 50% and 90% repolarization, and increased driving force for L-type Ca2+ current. Trpm4-/- mice; patch-clamp; membrane potential measurements; microfluorometry; contractility measurements; in vivo pressure-volume loop analysis Circulation research High 24226423
2016 In TLR4-activated microglia, Sur1-Trpm4 channels regulate Ca2+ influx to control NFAT nuclear translocation and downstream NOS2 transcription. Inhibiting or silencing Sur1 or Trpm4 increased [Ca2+]i but paradoxically decreased NFAT nuclear translocation via phosphorylation of CaMKII and calcineurin. In vivo and in vitro microglia; LPS activation; patch-clamp; calcium imaging; chromatin immunoprecipitation; co-immunoprecipitation; immunohistochemistry; qPCR; Griess assay; Trpm4-/- and Abcc8-/- mice Journal of neuroinflammation High 27246103
2021 NO/cGMP/PKG signaling causes vasodilation by inhibiting TRPM4 channel activity in cerebral artery smooth muscle cells. PKG phosphorylates IRAG, which then inhibits IP3R-mediated Ca2+ release from the SR, thereby reducing Ca2+-dependent TRPM4 activation. IRAG, PKG, and IP3Rs form a nanoscale signaling complex on the SR. IRAG knockdown diminished NO-mediated TRPM4 inhibition and vasodilation. Electrophysiology; Ca2+ imaging; pharmacological inhibition of sGC and PKG; siRNA knockdown of IRAG; superresolution microscopy; isolated cerebral artery myogenic response measurements Function (Oxford, England) High 34734188
2023 Na+ influx through SUR1-TRPM4 in perivascular astrocyte endfeet drives Ca2+ entry through NCX1 operating in reverse mode, raising intra-endfoot Ca2+ which stimulates calmodulin-dependent AQP4 translocation to the plasma membrane, causing water influx and brain swelling after ischemic stroke. Mouse ischemic stroke model; pharmacological inhibition of SUR1-TRPM4 and NCX1; astrocyte-specific gene deletion; Ca2+ imaging; AQP4 surface localization assays Science signaling High 37279286
2018 TRPM4 gain-of-function mutations (p.Ile1033Met and p.Ile1040Thr) in the S6 transmembrane domain, corresponding to the activation gate per cryo-EM structures, cause autosomal dominant progressive symmetric erythrokeratodermia. Mutant channels show pronounced baseline activity, enhanced Ca2+ sensitivity, and elevated resting membrane potential, and enhance keratinocyte proliferation. Genetic sequencing; cryo-EM structural analysis; patch-clamp electrophysiology of mutants; keratinocyte proliferation assays The Journal of investigative dermatology High 30528822
2016 The TRPM4 variant p.I376T causes gain of surface expression and increased current density in HEK293 cells, establishing a gain-of-expression/function mechanism for progressive familial heart block type I. Whole-cell patch-clamp; Western blot; surface expression analysis in HEK293 cells International journal of cardiology Medium 26820365
2011 TRPM4 silencing promotes GSK-3β-dependent degradation of β-catenin and reduces β-catenin/Tcf/Lef transcriptional activity, decreasing HeLa cell proliferation. TRPM4 overexpression increases cell proliferation and β-catenin levels. TRPM4 functions as a regulator of the β-catenin signaling pathway. siRNA knockdown; TRPM4 overexpression; Western blot for β-catenin phosphorylation; Tcf/Lef reporter assay; proliferation assay Journal of cellular physiology Medium 20625999
2017 TRPM4 silencing in PC3 prostate cancer cells decreases Akt1 phosphorylation, increases GSK-3β activity, and promotes β-catenin degradation, reducing nuclear β-catenin and Tcf/Lef transcription. The effect on Akt1 is mediated through the calcium/calmodulin-EGFR axis. siRNA knockdown; TRPM4 overexpression; Western blot for phosphorylated GSK-3β, β-catenin, Akt; Tcf/Lef reporter assay Molecular oncology Medium 28614631
2018 TRPM4 knockdown in PC3 prostate cancer cells reduces Snail1 expression and causes partial reversion of EMT (altered MMP9, E-cadherin/N-cadherin, vimentin), decreasing migration and invasion. TRPM4 overexpression in LNCaP cells increases Snail1, reduces E-cadherin, and increases migration. shRNA knockdown; TRPM4 overexpression; Western blot for EMT markers; migration/invasion assays Journal of cellular physiology Medium 30343491
2015 TRPM4 currents in primary cilia of renal mIMCD-3 cells have EC50 ~646 µM for Ca2+ at +100 mV, are inhibited by MgATP and 9-phenanthrol, are not permeable to Ca2+ or Cl-, and are modulated by PIP2. shRNA reduction of Trpm4 shortened primary cilia by 43%. Direct patch-clamp recording from excised primary cilia; shRNA knockdown; pharmacological characterization American journal of physiology. Renal physiology Medium 26290373
2016 U73122 (PLC inhibitor) is a potent agonist of TRPM4 channels that acts through covalent modification, independently of PLC, PIP2 depletion, and Ca2+. It activates endogenous TRPM4 in CHO, Jurkat, and HEK293T cells and recombinant human TRPM4. TRPM5 was insensitive to U73122, showing selectivity within the TRPM family. Whole-cell patch-clamp; pharmacological characterization; comparison of TRPM4, TRPM3, TRPM5 responses British journal of pharmacology Medium 27328745
2018 TRPM4 is present in TRPM4 is expressed in medial prefrontal cortex layer 2/3 pyramidal neurons and interneurons, localizing to soma and proximal dendrites but not the axon initial segment. A 9-phenanthrol-sensitive TRPM4-like current is active at resting membrane potential, and local somatic perfusion of 9-phenanthrol reduces basal current. Multiplex immunofluorescence; perforated patch-clamp; local superfusion experiments Frontiers in cellular neuroscience Medium 29440991
2021 TRPM4 in pancreatic acinar cells mediates Ca2+-dependent membrane depolarization (from -44.4 to -27.7 mV), which reduces the inward driving force for Ca2+ entry. TRPM4 KO or pharmacological inhibition (CBA) increases Ca2+ influx and augments Ca2+ oscillation amplitude induced by cerulein, identifying TRPM4 as a negative feedback regulator of Ca2+ entry. Trpm4-/- mice; patch-clamp (whole-cell and perforated); CBA pharmacological inhibition; Ca2+ imaging; cerulein stimulation The Journal of biological chemistry High 34329682
2022 TRPM4 mediates a Ca2+ overload-induced background current in ventricular cardiomyocytes. Trpm4-/- mice and meclofenamate (identified as a potent TRPM4 antagonist) both reduced Ca2+-dependent triggered arrhythmias in two proarrhythmic mouse models, establishing TRPM4 as a contributor to triggered cardiac arrhythmias. Trpm4-/- mice; compound screening; in vitro electrophysiology; in vivo intracardiac and telemetric ECG; meclofenamate pharmacology European heart journal High 35822895
2021 Selective deletion of TRPM4 in mouse cardiomyocytes reduces pressure overload-induced left ventricular hypertrophy by ~50%, identifying TRPM4 as a component of the mechanosensory signaling pathway that induces LVH in response to pressure overload. Cardiomyocyte-specific Trpm4 conditional KO mice; transverse aortic constriction model; cardiac morphology and function measurements eLife High 34190686
2023 Piezo1 and TRPM4 are functionally coupled in HL-1 atrial myocyte-like cells: Yoda1-induced Piezo1 activation alters action potential frequency, and this effect is significantly reduced by TRPM4 knockdown or pharmacological inhibition. siRNA knockdown of Piezo1 and TRPM4; 9-phenanthrol pharmacology; FluoVolt voltage imaging; Yoda1 agonist stimulation The Journal of physiology Medium 38098265
2023 TRPM4 plays a pivotal role in necrosis-inducing cancer therapy (ErSO/BHPI). CRISPR screen identified TRPM4 as essential for necrotic cell death; TRPM4 KO abolished ErSO-induced tumor regression in mice. Mechanistically, ErSO activates unfolded protein response (a-UPR), and TRPM4-mediated Na+ influx and cell swelling sustain and propagate lethal a-UPR hyperactivation. Genome-wide CRISPR-Cas9 screen; TRPM4 KO cells and in vivo tumor models; cell volume measurement; ATP depletion assay; macrophage activation assay Cancer research High 37522838
2025 TRPM4 persistent activation by the small molecule NC1 causes necrosis via sodium overload (NECSO). NC1 specifically activates human TRPM4 but not mouse TRPM4 due to differences in a transmembrane region identified by domain swapping and molecular docking. Gain-of-function cardiac arrhythmia mutations increase NECSO vulnerability. TRPM4-deficient cells are resistant to NC1-induced necrosis. TRPM4-deficient cells; domain swapping; molecular docking; cell death assays; compound screening for NECSO inhibitors Nature chemical biology High 39915626
2018 TRPM4 and TRPM5 are both required for taste transduction in type II taste receptor cells. Loss of either channel significantly impairs taste detection; loss of both abolishes detection of bitter, sweet, or umami stimuli. TRPM4 functions as a downstream component in these taste signaling pathways. TRPM4 KO and TRPM5 KO mice; double KO mice; live cell Ca2+ imaging; behavioral taste assays Proceedings of the National Academy of Sciences of the United States of America High 29311301
2018 TRPM4 and NCX2 functionally cooperate to control Ca2+-mediated MUC2 and MUC5AC mucin secretion. Blocking TRPM4 or NCX activity abrogated mucin secretion in colonic, bronchial, and cystic fibrosis tracheal cells. TRPM4 and NCXs are both required for regulated mucin secretion. TRPM4 and NCX pharmacological inhibition; mucin secretion assays in HT29-18N2, NHBE, and CFT1-LC3 cells; Western blot The Journal of biological chemistry Medium 30482841
2020 TRPM4 currents in ventricular fibroblasts from heart failure patients are more than 2-fold larger than controls. TGFβ1 treatment of control fibroblasts increases TRPM4 current within 24 hours, suggesting TGFβ1 upregulates TRPM4 expression and links TRPM4 to cardiac fibrogenesis. Patch-clamp electrophysiology of primary human fibroblasts; Western blot; TGFβ1 stimulation Pflugers Archiv : European journal of physiology Medium 33594499
2022 p53 and p63γ repress TRPM4 promoter activity. Loss of p53 increases TRPM4 mRNA, protein, and Na+ currents in colorectal cancer cells. Transient p53 overexpression decreases TRPM4-mediated currents. TRPM4 KO mimics the effect of p53 on store-operated Ca2+ entry and cell cycle distribution. CRISPR-Cas9 KO; p53/p63γ overexpression; promoter-reporter assays; patch-clamp; Ca2+ imaging; cell cycle analysis Cell calcium Medium 35500522
2022 In colorectal cancer cells, TRPM4 overexpression enhances Ca2+ influx to activate calpain-mediated proteolysis of FAK, and suppresses PI3K/Akt/mTOR signaling, reducing migration and invasion. Calpain inhibition relieves FAK suppression and reverses the migration inhibitory effect, placing TRPM4 upstream of Ca2+/calpain/FAK axis. TRPM4 overexpression; calpain inhibition; Western blot for FAK, Akt, PI3K, mTOR; migration assays; in vivo tumor model International journal of biological sciences Medium 36147460
2019 TRPM4 in NF-κB-activated brain endothelial cells is opened by tPA in a plasmin-, PAR1-, TRPC3-, and Ca2+-dependent manner, and this SUR1-TRPM4 channel activity is required for tPA-induced phasic (but not tonic) MMP-9 secretion. NF-κB activation of brain endothelial cells; patch-clamp electrophysiology; ELISA and zymography for MMP-9; genetic and pharmacological inhibition of SUR1-TRPM4 and TRPC3; Ca2+ imaging PloS one Medium 29617457
2016 Heterologously expressed TRPM4 assembles as a functional tetramer. Purified TRPM4-eGFP in detergent micelles was found to be tetrameric by crosslinking, native gel electrophoresis, multi-angle laser light scattering, and electron microscopy. Liposome-reconstituted TRPM4-eGFP exhibited single-channel activity inhibitable by flufenamic acid. Protein purification; crosslinking; native PAGE; multi-angle laser light scattering; electron microscopy; single-channel electrophysiology of proteoliposomes Scientific reports High 26785754
2023 TRPM4 and TRPV4 functionally couple in human trabecular meshwork (TM) cells: TRPV4 agonist (GSK1016790A) activates TRPM4-mediated monovalent cation current and Ca2+ oscillations. TRPM4 silencing antagonized TRPV4-evoked oscillatory signaling; co-expression of TRPV4 and TRPM4 in HEK-293 cells reconstituted oscillations. siRNA knockdown; electrophysiology; Ca2+ imaging; heterologous co-expression in HEK-293 cells; immunofluorescence Frontiers in immunology Medium 35432302
2023 Age-dependent deficiency of TRPM4 currents in cerebral artery smooth muscle cells from Col4a1 mutant mice (Gould syndrome model) underlies impaired vascular myogenic response. Excess PI3K activity consumes PIP2 (required for TRPM4 activity). Dialyzing cells with PIP2 or inhibiting PI3K restored TRPM4 currents and rescued myogenic response. TGF-β signaling drives PI3K hyperactivity to deplete PIP2. Patch-clamp of native SMCs from Col4a1 mutant mice; PIP2 dialysis; PI3K inhibitors; TGF-β receptor inhibition; myogenic response measurements Proceedings of the National Academy of Sciences of the United States of America High 36693102
2020 TRPM4 contributes to plateau potentials and persistent firing in thalamic reticular nucleus neurons, driven by Ca2+ influx through T-type Ca2+ channels. Pharmacological blockade of TRPM4 reduced plateau potentials and slow oscillatory activity. Thalamic slice electrophysiology; pharmacological inhibition of TRPM4; T-type Ca2+ channel blockers; recording in adult mice The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 32414784
2018 TRPM4 channels contribute to respiratory motor pattern formation (amplitude of inspiratory motoneuronal activity) but not rhythmogenesis in pre-Bötzinger complex inspiratory neurons. TRPM4 mRNA is expressed in these neurons. Pharmacological TRPM4 inhibition reduced inspiratory burst amplitude without altering frequency in both in vitro slices and in situ preparations. Single-cell multiplex RT-PCR; TRPM4 pharmacological inhibition; in vitro medullary slice recordings; in situ brainstem-spinal cord preparation recordings; calcium imaging eNeuro Medium 29435486
2012 TRPM4 ablation dramatically increased mouse mortality in cecal ligation and puncture sepsis due to impaired macrophage Ca2+ mobilization, downregulated AKT signaling, and decreased phagocytic activity, resulting in bacterial overgrowth. Trpm4-/- neutrophils showed no alteration in function or Ca2+ mobilization, demonstrating cell-type-specific Ca2+ regulatory mechanisms. Trpm4-/- mice; cecal ligation and puncture model; Ca2+ imaging; AKT signaling analysis; phagocytosis assays; bacterial enumeration Journal of immunology (Baltimore, Md. : 1950) High 22933633

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate. The EMBO journal 258 16424899
2009 De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nature medicine 178 19169264
2012 TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature medicine 170 23160238
2017 Structures of the calcium-activated, non-selective cation channel TRPM4. Nature 163 29211714
2012 The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel. The Journal of biological chemistry 154 23255597
2017 Electron cryo-microscopy structure of a human TRPM4 channel. Nature 149 29211723
2006 TRPM4 controls insulin secretion in pancreatic beta-cells. Cell calcium 147 16806463
2006 TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells. Cardiovascular research 138 17188667
2007 Protein kinase C regulates vascular myogenic tone through activation of TRPM4. American journal of physiology. Heart and circulatory physiology 137 17293488
2020 Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants. Science (New York, N.Y.) 122 33033186
2018 TRPM4 and TRPM5 are both required for normal signaling in taste receptor cells. Proceedings of the National Academy of Sciences of the United States of America 114 29311301
2017 SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia 113 28906027
2007 Insights into TRPM4 function, regulation and physiological role. Handbook of experimental pharmacology 106 17217063
2010 Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization. Journal of immunology (Baltimore, Md. : 1950) 85 20656926
2014 The TRPM4 channel inhibitor 9-phenanthrol. British journal of pharmacology 84 24433510
2015 Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts. Journal of neuropathology and experimental neurology 83 26172285
2008 TRPM4 regulates migration of mast cells in mice. Cell calcium 82 19046767
2018 Structure of full-length human TRPM4. Proceedings of the National Academy of Sciences of the United States of America 81 29463718
2012 The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis. Journal of immunology (Baltimore, Md. : 1950) 81 22933633
2013 TRPM4 inhibition promotes angiogenesis after ischemic stroke. Pflugers Archiv : European journal of physiology 77 24043570
2011 The non-selective monovalent cationic channels TRPM4 and TRPM5. Advances in experimental medicine and biology 75 21290294
2017 TRPM4 regulates Akt/GSK3-β activity and enhances β-catenin signaling and cell proliferation in prostate cancer cells. Molecular oncology 74 28614631
2016 The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. Journal of neuroinflammation 72 27246103
2013 Increased β-adrenergic inotropy in ventricular myocardium from Trpm4-/- mice. Circulation research 69 24226423
2012 TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology. Biochemical pharmacology 69 22750058
2014 Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations. PloS one 67 25531103
2015 TRPM4 in cardiac electrical activity. Cardiovascular research 63 26272755
2011 TRPM4 enhances cell proliferation through up-regulation of the β-catenin signaling pathway. Journal of cellular physiology 63 20625999
2014 TRPM4. Handbook of experimental pharmacology 58 24756717
2018 TRPM4 channel is involved in regulating epithelial to mesenchymal transition, migration, and invasion of prostate cancer cell lines. Journal of cellular physiology 55 30343491
2025 Persistent activation of TRPM4 triggers necrotic cell death characterized by sodium overload. Nature chemical biology 52 39915626
2019 TRPM4 channel and cancer. Cancer letters 52 30980865
2014 Ghrelin inhibits BSCB disruption/hemorrhage by attenuating MMP-9 and SUR1/TrpM4 expression and activation after spinal cord injury. Biochimica et biophysica acta 51 25261791
2016 Direct modulation of TRPM4 and TRPM3 channels by the phospholipase C inhibitor U73122. British journal of pharmacology 50 27328745
2003 Identification and characterization of the murine TRPM4 channel. Biochemical and biophysical research communications 50 12893253
2021 TRPM4 in Cancer-A New Potential Drug Target. Biomolecules 49 33562811
2019 TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells. Molecular oncology 48 31441200
2013 TRPM4 channels in smooth muscle function. Pflugers Archiv : European journal of physiology 48 23443854
2018 SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells. PloS one 46 29617457
2018 MicroRNA-150 suppresses epithelial-mesenchymal transition, invasion, and metastasis in prostate cancer through the TRPM4-mediated β-catenin signaling pathway. American journal of physiology. Cell physiology 46 30566393
2016 Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. International journal of cardiology 46 26820365
2018 Gain-of-Function Mutations in TRPM4 Activation Gate Cause Progressive Symmetric Erythrokeratodermia. The Journal of investigative dermatology 44 30528822
2018 Role of the TRPM4 Channel in Cardiovascular Physiology and Pathophysiology. Cells 43 29914130
2014 TRPM4 channels couple purinergic receptor mechanoactivation and myogenic tone development in cerebral parenchymal arterioles. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 43 25099756
2023 Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke. Science signaling 42 37279286
2015 TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres. The Journal of physiology 40 26548780
2013 TRPM4 channels in the cardiovascular system. Current opinion in pharmacology 39 24721656
2019 SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia. Neuroscience letters 37 31899311
2013 Biochemical, single-channel, whole-cell patch clamp, and pharmacological analyses of endogenous TRPM4 channels in HEK293 cells. Neuroscience letters 37 23428507
2020 TRPM4 is overexpressed in breast cancer associated with estrogen response and epithelial-mesenchymal transition gene sets. PloS one 36 32484822
2018 Non-Invasive Multimodality Imaging Directly Shows TRPM4 Inhibition Ameliorates Stroke Reperfusion Injury. Translational stroke research 36 29569041
2019 TRPM4-specific blocking antibody attenuates reperfusion injury in a rat model of stroke. Pflugers Archiv : European journal of physiology 35 31664513
2014 Glycosylation of TRPM4 and TRPM5 channels: molecular determinants and functional aspects. Frontiers in cellular neuroscience 35 24605085
2018 Sodium channel TRPM4 and sodium/calcium exchangers (NCX) cooperate in the control of Ca2+-induced mucin secretion from goblet cells. The Journal of biological chemistry 34 30482841
2020 HIV-1 Vpr-Induced Proinflammatory Response and Apoptosis Are Mediated through the Sur1-Trpm4 Channel in Astrocytes. mBio 32 33293383
2022 TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias. European heart journal 31 35822895
2017 TRPM4 non-selective cation channel variants in long QT syndrome. BMC medical genetics 31 28315637
2015 Enhanced β-adrenergic cardiac reserve in Trpm4⁻/⁻ mice with ischaemic heart failure. Cardiovascular research 30 25600961
2021 The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy. eLife 29 34190686
2018 Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits. eNeuro 28 29435486
2015 PIP2 and PIP3 interact with N-terminus region of TRPM4 channel. Biophysical chemistry 28 26071843
2022 Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia. Molecular neurobiology 27 35972671
2021 Species-Specific Effects of Cation Channel TRPM4 Small-Molecule Inhibitors. Frontiers in pharmacology 27 34335274
2023 Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy-Induced Necrosis. Cancer research 26 37522838
2020 Inherited Cardiac Arrhythmia Syndromes: Focus on Molecular Mechanisms Underlying TRPM4 Channelopathies. Cardiovascular therapeutics 26 33381229
2022 A novel methylated cation channel TRPM4 inhibited colorectal cancer metastasis through Ca2+/Calpain-mediated proteolysis of FAK and suppression of PI3K/Akt/mTOR signaling pathway. International journal of biological sciences 25 36147460
2021 Nitric Oxide Signals Through IRAG to Inhibit TRPM4 Channels and Dilate Cerebral Arteries. Function (Oxford, England) 25 34734188
2019 EB1- and EB2-dependent anterograde trafficking of TRPM4 regulates focal adhesion turnover and cell invasion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 31112396
2021 Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel-Part 2: TRPM4 in Health and Disease. Pharmaceuticals (Basel, Switzerland) 24 35056097
2020 Small Molecular Inhibitors Block TRPM4 Currents in Prostate Cancer Cells, with Limited Impact on Cancer Hallmark Functions. Journal of molecular biology 24 33058873
2012 On potential interactions between non-selective cation channel TRPM4 and sulfonylurea receptor SUR1. The Journal of biological chemistry 24 22291026
2022 Emergent Temporal Signaling in Human Trabecular Meshwork Cells: Role of TRPV4-TRPM4 Interactions. Frontiers in immunology 23 35432302
2015 Physiological functions of the TRPM4 channels via protein interactions. BMB reports 23 25441424
2015 A TRPM4-dependent current in murine renal primary cilia. American journal of physiology. Renal physiology 22 26290373
2021 Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients. Pflugers Archiv : European journal of physiology 21 33594499
2020 Comparison of Anti-oncotic Effect of TRPM4 Blocking Antibody in Neuron, Astrocyte and Vascular Endothelial Cell Under Hypoxia. Frontiers in cell and developmental biology 21 33195194
2020 Aberrant TRPM4 expression in MLL-rearranged acute myeloid leukemia and its blockade induces cell cycle arrest via AKT/GLI1/Cyclin D1 pathway. Cellular signalling 20 32320859
2020 TRPM4 inhibition improves spatial memory impairment and hippocampal long-term potentiation deficit in chronic cerebral hypoperfused rats. Behavioural brain research 20 32619565
2023 Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome. Proceedings of the National Academy of Sciences of the United States of America 19 36693102
2022 Germline Variants of CYBA and TRPM4 Predispose to Familial Colorectal Cancer. Cancers 19 35158942
2022 p53 alters intracellular Ca2+ signaling through regulation of TRPM4. Cell calcium 19 35500522
2019 Glibenclamide, a Sur1-Trpm4 antagonist, does not improve outcome after collagenase-induced intracerebral hemorrhage. PloS one 19 31042750
2017 The TRPM4 channel is functionally important for the beneficial cardiac remodeling induced by endurance training. Journal of muscle research and cell motility 19 28224334
2023 Functional coupling between Piezo1 and TRPM4 influences the electrical activity of HL-1 atrial myocytes. The Journal of physiology 18 38098265
2021 TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells. The Journal of biological chemistry 18 34329682
2018 Subcellular Localization and Activity of TRPM4 in Medial Prefrontal Cortex Layer 2/3. Frontiers in cellular neuroscience 18 29440991
2018 Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn-Schmiedeberg's archives of pharmacology 18 30054681
2017 Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 28214884
2011 Basal protein kinase Cδ activity is required for membrane localization and activity of TRPM4 channels in cerebral artery smooth muscle cells. Channels (Austin, Tex.) 18 21406958
2009 Cloning and characterization of rat transient receptor potential-melastatin 4 (TRPM4). Biochemical and biophysical research communications 18 19945433
2020 TRPM4 non-selective cation channel in human atrial fibroblast growth. Pflugers Archiv : European journal of physiology 17 33047172
2024 Sodium-Permeable Ion Channels TRPM4 and TRPM5 are Functional in Human Gastric Parietal Cells in Culture and Modulate the Cellular Response to Bitter-Tasting Food Constituents. Journal of agricultural and food chemistry 16 38378185
2016 Heterologously-expressed and Liposome-reconstituted Human Transient Receptor Potential Melastatin 4 Channel (TRPM4) is a Functional Tetramer. Scientific reports 16 26785754
2021 Investigation of Novel Small Molecular TRPM4 Inhibitors in Colorectal Cancer Cells. Cancers 15 34771564
2020 Genetic background influences expression and function of the cation channel TRPM4 in the mouse heart. Basic research in cardiology 15 33205255
2022 Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel-Part 1: Modulation of TRPM4. Pharmaceuticals (Basel, Switzerland) 14 35056138
2021 Development and characterization of a monoclonal antibody blocking human TRPM4 channel. Scientific reports 14 34002002
2020 TRPM4 Conductances in Thalamic Reticular Nucleus Neurons Generate Persistent Firing during Slow Oscillations. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 32414784
2018 Functional characterization of TRPM4 variants identified in sudden unexpected natural death. Forensic science international 14 30391667
2025 Identification of a binding site for small molecule inhibitors targeting human TRPM4. Nature communications 13 39828793

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