Affinage

TRPM7

Transient receptor potential cation channel subfamily M member 7 · UniProt Q96QT4

Length
1865 aa
Mass
212.7 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM7 is a ubiquitously expressed bifunctional 'chanzyme' that couples a divalent cation-permeable channel (Ca²⁺, Mg²⁺, Zn²⁺) to a C-terminal α-kinase domain, integrating ion transport with phosphorylation-dependent signaling to control cell viability, migration, immune cell function, and gene expression. The channel is constitutively suppressed by intracellular Mg²⁺ binding at a conserved lower-gate residue (N1097) and by Mg·ATP, requires PIP2, and is regulated by assembly into native complexes with CNNM1–4 metal transporters and the small GTPase ARL15, which tune divalent cation entry; palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls surface trafficking (PMID:35389104, PMID:34766907, PMID:36027648, PMID:11385574). The α-kinase domain undergoes proteolytic cleavage, and the released fragment translocates to the nucleus where it phosphorylates histone H3 at Ser10 at target-gene promoters in association with Polycomb complexes, while cytoplasmic substrates including myosin IIA heavy chain, annexin 1, cofilin, RhoA, and CREB control actomyosin contractility, cell migration, synapse density, mast cell degranulation, platelet activation, and neutrophil transmigration (PMID:24855944, PMID:16407977, PMID:29924992, PMID:26660477, PMID:29146750). A gain-of-function A931T mutation generating a gating-pore omega current in TRPM7 causes familial trigeminal neuralgia, and cryo-EM structures have delineated distinct activation mechanisms by agonists versus gain-of-function mutations and identified a selective-inhibitor binding pocket in the closed state (PMID:36095216, PMID:37156763).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Establishing that TRPM7 constitutes a novel class of Mg·ATP-regulated divalent cation channel essential for cell viability resolved the molecular identity of the ubiquitous Mg²⁺-inhibited current and demonstrated that channel loss is cell-lethal.

    Evidence Heterologous expression with patch-clamp in HEK-293 and targeted gene deletion in DT40 B cells

    PMID:11385574

    Open questions at the time
    • Structural basis of Mg·ATP inhibition unresolved
    • Channel vs. kinase contribution to lethality not separated
  2. 2004 High

    Identification of annexin 1 and subsequently myosin IIA heavy chain as direct TRPM7 kinase substrates established that the kinase domain has autonomous signaling functions beyond ion conduction, linking it to Ca²⁺-dependent membrane dynamics and actomyosin contractility.

    Evidence In vitro kinase assays with site-directed mutagenesis (annexin 1 Ser5); co-IP plus kinase-dead mutant analysis and live-cell imaging for myosin IIA

    PMID:15485879 PMID:16407977

    Open questions at the time
    • Full kinase substrate repertoire unknown
    • In vivo relevance of annexin 1 phosphorylation not tested
  3. 2006 High

    Demonstration that TRPM6 and TRPM7 form distinct homomeric and heteromeric channels with different permeation and pharmacological profiles clarified their non-redundant physiological roles in divalent cation homeostasis.

    Evidence Whole-cell and single-channel patch-clamp of homo- and heteromeric channels with pharmacological profiling (2-APB)

    PMID:16636202

    Open questions at the time
    • Stoichiometry and assembly rules of heteromeric channels not determined
    • Tissue-specific ratio of homo- vs. heteromeric channels unknown
  4. 2009 High

    Showing that hippocampal TRPM7 knockdown prevents delayed neuronal death after global ischemia without affecting basal synaptic function established TRPM7 as a mediator of ischemic neuronal injury in vivo.

    Evidence Viral shRNA delivery to rat CA1 neurons, electrophysiology (LTP), behavioral testing, histology

    PMID:19734892

    Open questions at the time
    • Downstream death pathway (Ca²⁺ vs. Zn²⁺ overload) not delineated
    • Kinase vs. channel contribution to ischemic death not separated
  5. 2011 High

    Rescue of TRPM7-knockdown migration defects by the Mg²⁺ transporter SLC41A2 identified Mg²⁺ as the critical effector ion through which TRPM7 controls Rac/Cdc42 activation and polarized cell migration, separating Mg²⁺-dependent from Ca²⁺-dependent channel functions.

    Evidence siRNA knockdown with GTPase activation pulldowns, rescue with kinase-dead TRPM7 and SLC41A2 overexpression, wound-healing assays

    PMID:21208190

    Open questions at the time
    • Direct Mg²⁺-sensing mechanism linking Rac/Cdc42 activation not identified
    • In vivo validation in migratory cell types lacking
  6. 2014 High

    Discovery that the TRPM7 kinase domain is proteolytically cleaved, translocates to the nucleus, and phosphorylates histone H3 at Ser10 at target promoters revealed an unanticipated mechanism by which an ion channel directly regulates chromatin and gene expression.

    Evidence Biochemical fractionation, co-IP with Polycomb proteins, mass spectrometry, in vitro histone kinase assay, Zn²⁺ imaging, transcriptomics

    PMID:24855944

    Open questions at the time
    • Protease responsible for cleavage not identified
    • Genome-wide map of H3S10ph targets incomplete
    • Regulation of cleavage kinetics unknown
  7. 2014 High

    TRPM6 kinase was found to cross-phosphorylate TRPM7 (but not vice versa), altering TRPM7 trafficking and growth under hypomagnesemia, establishing a directional kinase crosstalk between the two chanzymes.

    Evidence Kinase assays, trafficking analysis, kinase-dead TRPM6 complementation in HEK-293 and DT40 cells

    PMID:24858416

    Open questions at the time
    • Phosphorylation sites on TRPM7 not mapped
    • Physiological relevance in epithelial Mg²⁺ transport not confirmed in vivo
  8. 2016 High

    Genetic separation of kinase and channel functions in mouse mast cells showed that kinase activity (not channel conductance) controls IgE-dependent degranulation and histamine release by modulating sensitivity to intracellular Ca²⁺ and extracellular Mg²⁺.

    Evidence Comparison of TRPM7+/ΔK and kinase-dead (KR) mouse mast cells, exocytosis and histamine release assays

    PMID:26660477

    Open questions at the time
    • Direct kinase substrate in mast cell exocytic machinery not identified
  9. 2017 High

    In vivo studies using kinase-dead knock-in mice revealed that TRPM7 kinase controls platelet activation via Syk/PLCγ phosphorylation and PIP2 metabolism, protecting against arterial thrombosis and ischemic stroke, and independently maintains synapse density through cofilin phosphorylation.

    Evidence Trpm7R/R kinase-dead mice with platelet assays, phosphoproteomics, in vivo thrombosis models; hippocampal conditional KO with α-kinase rescue, LTP, and behavioral tests

    PMID:29146750 PMID:29924992

    Open questions at the time
    • Full phosphoproteomic substrate spectrum in platelets and neurons not defined
    • Whether kinase effects on cofilin are direct or via intermediate kinases unclear
  10. 2018 High

    B cell-specific TRPM7 knockout revealed that channel-mediated Mg²⁺ influx is essential for B cell development at the pro-B stage, while both channel and kinase contribute to BCR signaling, antigen gathering, and presentation to T cells.

    Evidence B cell-specific KO mice, flow cytometry of developmental stages, Mg²⁺ rescue, kinase-dead B cell lines with BCR signaling and antigen presentation assays

    PMID:29871911 PMID:29871912

    Open questions at the time
    • How Mg²⁺ influx specifically permits pro-B to pre-B transition is mechanistically unresolved
  11. 2019 High

    TRPM7 was shown to control the RhoA–actin–MRTF-A/SRF transcriptional axis through both Mg²⁺ influx and direct RhoA phosphorylation by the kinase, connecting channel activity to gene expression programs governing cytoskeletal remodeling.

    Evidence CRISPR KO, pharmacological inhibition (NS8593), RhoA activity assays, co-IP of MRTF-A/Filamin A

    PMID:31844251

    Open questions at the time
    • RhoA phosphorylation site by TRPM7 kinase not mapped
    • Relative contribution of Mg²⁺ vs. kinase in different cell types unknown
  12. 2021 High

    Purification of native TRPM7 complexes from brain identified CNNM1–4 and ARL15 as stable partners that modulate channel activity, and subsequent studies showed PRL phosphatases tune this complex to couple cellular Mg²⁺ sensing to TRPM7 function.

    Evidence Multi-epitope affinity purification, quantitative mass spectrometry, reconstitution with patch-clamp; genetically encoded Mg²⁺ reporter, PRL-1/2 KO cells, co-IP

    PMID:34766907 PMID:34928937 PMID:36972446

    Open questions at the time
    • Structural basis of CNNM–TRPM7 interface unknown
    • Whether CNNM regulation of TRPM7 operates identically in all tissues not tested
  13. 2022 High

    Identification of N1097 as the intracellular Mg²⁺-binding site in the lower channel gate provided the first structural explanation for how physiological Mg²⁺ suppresses TRPM7 opening.

    Evidence Site-directed mutagenesis, single-channel electrophysiology, molecular dynamics simulations

    PMID:35389104

    Open questions at the time
    • Full-length high-resolution structure with Mg²⁺ at this site not yet available
    • Cooperativity among four subunit gate sites not characterized
  14. 2022 High

    Demonstrating that TRPM7 localizes to phagosomes, conducts a pH-activated cationic current, and sustains phagosomal acidification established a previously unknown role for TRPM7 in macrophage efferocytosis.

    Evidence siRNA screen, perforated patch electrophysiology, genetically encoded phagosomal Ca²⁺ sensor in mice, cargo digestion assays

    PMID:35680919

    Open questions at the time
    • Identity of the pH sensor within TRPM7 not determined
    • Whether phagosomal TRPM7 is palmitoylation-dependent not tested
  15. 2022 High

    Discovery that palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls TRPM7 ER exit and surface residence revealed a post-translational trafficking switch regulating channel availability.

    Evidence RUSH trafficking system, palmitoylation-site mutagenesis, zDHHC knockdown, Ca²⁺ uptake assays

    PMID:36027648

    Open questions at the time
    • Dynamic regulation of palmitoylation/depalmitoylation cycle not characterized
    • Which thioesterase depalmitoylates TRPM7 unknown
  16. 2022 High

    A TRPM7 gain-of-function mutation (A931T) was linked to familial trigeminal neuralgia by generating a gating-pore omega current that lowers neuronal firing threshold, providing the first Mendelian disease association for TRPM7.

    Evidence Whole-exome sequencing, patch-clamp of mutant channels in HEK-293 and trigeminal ganglion neurons, Na⁺/Ca²⁺ imaging

    PMID:36095216

    Open questions at the time
    • Penetrance and prevalence in other trigeminal neuralgia cohorts not established
    • Therapeutic targetability of the omega current not tested
  17. 2023 High

    Cryo-EM structures of TRPM7 in closed, agonist-bound, and gain-of-function states delineated two distinct activation mechanisms and identified a selective-inhibitor binding pocket, providing an atomic framework for drug design.

    Evidence Cryo-EM, functional mutagenesis, molecular dynamics simulations, electrophysiology

    PMID:37156763

    Open questions at the time
    • Structure of TRPM7 in complex with CNNM/ARL15 not resolved
    • Kinase-domain conformation relative to channel in full-length structure not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease that cleaves the kinase domain, the full substrate repertoire of the kinase in different tissues, the structural basis of the TRPM7–CNNM–ARL15 regulatory complex, and whether channel and kinase activities can be therapeutically targeted independently.
  • Protease identity for kinase cleavage unknown
  • Tissue-specific kinase substrate mapping incomplete
  • No TRPM7–CNNM–ARL15 co-structure available
  • Selective kinase-only or channel-only inhibitors not yet validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0005215 transporter activity 7 GO:0016740 transferase activity 6 GO:0042393 histone binding 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 2 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 5 R-HSA-382551 Transport of small molecules 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-109582 Hemostasis 1
Partners
ACTN1ANXA1ARL15CNNM1CNNM3MYH9TRPM6ZDHHC17
Complex memberships
TRPM6/TRPM7 heteromerTRPM7-CNNM-ARL15

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TRPM7 (LTRPC7) is a Mg·ATP- and Mg·GTP-regulated, voltage-independent divalent cation channel permeable to Ca2+ and Mg2+; intracellular Mg-nucleotides strongly suppress channel activity; targeted deletion in DT40 B cells is lethal, establishing TRPM7 as essential for cell viability. Heterologous expression in HEK-293 cells with whole-cell patch-clamp electrophysiology; targeted gene deletion in DT40 B cells Nature High 11385574
2004 TRPM7 kinase phosphorylates annexin 1 at Ser5 within its N-terminal amphipathic alpha-helix in a Ca2+-stimulated manner, identifying annexin 1 as the first endogenous substrate of the TRPM7 kinase domain. In vitro kinase assay using TRPM7 kinase domain; phosphorylation confirmed in cell extracts overexpressing TRPM7; site identified by mutagenesis The Journal of biological chemistry High 15485879
2006 TRPM7 activation by bradykinin leads to a Ca2+- and kinase-dependent interaction with the actomyosin cytoskeleton; TRPM7 kinase phosphorylates myosin IIA heavy chain; low-level overexpression increases intracellular Ca2+, promotes cell spreading, adhesion, focal adhesion formation, and kinase-dependently drives transformation of focal adhesions into podosomes. Live-cell imaging, Ca2+ imaging, kinase assays, co-immunoprecipitation, pharmacological inhibition of myosin II, overexpression/kinase-dead mutant analysis The EMBO journal High 16407977
2006 TRPM6 forms functional homomeric channels with distinct divalent cation permeability profile, pH sensitivity, and unitary conductance from TRPM7; TRPM6 and TRPM7 also form heteromeric TRPM6/7 complexes with intermediate properties; 2-APB differentially modulates TRPM6 (activation) vs. TRPM7 (inhibition) channels. Heterologous expression with whole-cell and single-channel patch-clamp electrophysiology; pharmacological profiling The Journal of general physiology High 16636202
2009 Virally mediated shRNA suppression of TRPM7 in hippocampal CA1 neurons in rats prevents delayed neuronal death after global brain ischemia without impairing LTP or memory under basal conditions, demonstrating TRPM7 mediates ischemia-induced neuronal death in vivo. In vivo viral vector shRNA delivery, electrophysiology (LTP), behavioral tasks, histology Nature neuroscience High 19734892
2011 TRPM7 channel activity is inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) during phospholipase C-mediated signaling; regulation by Mg-nucleotides and cAMP/PKA requires a functional endogenous kinase domain; the kinase domain may autophosphorylate TRPM7. Patch-clamp electrophysiology, pharmacological manipulation, kinase-domain mutant analysis (reviewed/consolidated) Advances in experimental medicine and biology Medium 21290295
2011 TRPM7 depletion by RNAi alters cell morphology, disrupts the cytoskeleton, and abolishes Rac and Cdc42 activation upon wound-healing stimulus, impairing polarized cell migration; Mg2+ transporter SLC41A2 expression rescues these defects, indicating Mg2+ is the critical ion mediating TRPM7 control of polarized movement. RNAi knockdown, pulldown GTPase activation assays (Rac/Cdc42), rescue with kinase-dead mutant and SLC41A2 overexpression, wound-healing assay The Biochemical journal High 21208190
2013 TRPM7 channel activity is inhibited by intracellular chloride and bromide in synergy with Mg2+, acting through the ATP-binding site of the kinase domain; iodide is the strongest inhibitor at physiological Mg2+ and inhibits endogenous TRPM7-like currents in MCF-7 breast cancer cells. Whole-cell patch-clamp electrophysiology with intracellular halide dialysis, kinase-domain mutant analysis Cellular and molecular life sciences High 23471296
2014 TRPM7 kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner; the cleaved kinase fragments (M7CKs) translocate to the nucleus, bind chromatin-remodeling complexes including Polycomb group proteins, and phosphorylate histones (H3Ser10) at promoters of TRPM7-dependent genes; cytosolic free Zn2+ is TRPM7-dependent and regulates M7CK binding to zinc-finger transcription factors. Biochemical fractionation, co-immunoprecipitation, mass spectrometry, in vitro kinase assay on histones, Zn2+ imaging, transcriptomics Cell High 24855944
2014 TRPM7 channel activity produces localized Ca2+ microdomains ('sparks') at the ventral plasma membrane via extracellular Ca2+ influx; TRPM7 promotes invadosome formation independently of Ca2+ influx, instead acting through actomyosin contractility regulation. TIRF Ca2+ fluorometry, TRPM7 inhibitor (waixenicin A) application, automated Ca2+ spark analysis, invadosome quantification Cell calcium High 24176224
2014 TRPM7 channel activator naltriben acts through a site in or near the TRP domain; naltriben activates TRPM7 without prior Mg2+ depletion and even under low PIP2 conditions; kinase-domain and pore mutants indicate activation site is distinct from the kinase domain. Aequorin bioluminescence screen, whole-cell patch-clamp, TRPM7 domain mutant analysis Pflugers Archiv High 24633576
2014 TRPM7 co-precipitates and co-localizes with F-actin and α-actinin-1 at neuronal growth cones; blocking TRPM7 channel conductance reduces Ca2+ influx and accelerates axonal polarization and outgrowth, demonstrating that TRPM7-mediated Ca2+ influx inhibits axonal outgrowth via the F-actin/α-actinin-1 complex. Co-immunoprecipitation, immunofluorescence, shRNA knockdown, waixenicin A pharmacological blockade, Ca2+ imaging Molecular neurobiology High 25502295
2016 TRPM7 kinase activity (not channel activity) regulates mast cell degranulation and histamine release; TRPM7 kinase modulates sensitivity to intracellular Ca2+ and extracellular Mg2+ during IgE-dependent exocytosis, and affects granule mobility/contents. Comparison of TRPM7+/ΔK and TRPM7KR (kinase-dead point mutant) mouse mast cells; exocytosis assays, histamine release measurements The Journal of physiology High 26660477
2016 Aldosterone increases TRPM7 plasma membrane expression and current through a mineralocorticoid receptor (MR)-dependent genomic cascade involving SGK1; this upregulation requires a functioning TRPM7 α-kinase domain, as kinase-dead K1648R-TRPM7 is unresponsive to aldosterone. Whole-cell patch-clamp, cell-surface biotinylation, pharmacological blockade of MR (eplerenone) and SGK1 (GSK-650394), kinase-dead mutant expression The Journal of biological chemistry High 27466368
2016 The coiled-coil domain of TRPM7 is required for channel regulation by intracellular Mg2+ and Mg·ATP; C-terminal truncation mutants of zebrafish TRPM7 losing the coiled-coil domain show altered Mg-nucleotide sensitivity. C-terminal truncation mutant analysis by whole-cell patch-clamp electrophysiology in heterologous expression system Scientific reports High 27628598
2017 TRPM7 kinase activity (not channel activity itself) regulates store-operated calcium entry (SOCE)/CRAC currents in B lymphocytes; TRPM7 channel activity is required to maintain endoplasmic reticulum Ca2+ store levels at rest and for refilling after Ca2+ signaling events. TRPM7-/- DT40 B cells, kinase-deficient TRPM7 mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ imaging, patch-clamp of ICRAC The Journal of physiology High 28130783
2017 A point mutation in the TRPM7 kinase domain deleting kinase activity in mice causes impaired PIP2 metabolism and reduced Ca2+ mobilization in platelets in response to GPVI, CLEC-2, and PAR receptors; altered Syk and phospholipase Cγ2/β3 phosphorylation accounts for the defect; TRPM7 kinase-dead mice are protected from arterial thrombosis and ischemic stroke. Kinase-dead knock-in mice (Trpm7R/R), platelet activation assays, phosphoproteomics, in vivo thrombosis and stroke models Arteriosclerosis, thrombosis, and vascular biology High 29146750
2017 TRPM7 kinase domain is essential for normal synapse density; re-expression of the α-kinase domain alone (without channel) rescues synapse density, plasticity, and memory in TRPM7 conditional knockout mice, likely through kinase-mediated phosphorylation of cofilin. Hippocampal-specific TRPM7 knockdown/conditional KO in mice, electrophysiology (LTP), behavioral tests, rescue with α-kinase domain construct, cofilin phosphorylation assays Cell reports High 29924992
2017 TRPM7 kinase activity in ameloblasts phosphorylates CREB directly (shown by co-immunoprecipitation); kinase-inactive knock-in mice exhibit defective ameloblast differentiation with impaired phosphorylation of Smad1/5/9, p38, and CREB at the pre-secretory stage, demonstrating kinase-dependent control of tooth enamel formation. TRPM7 kinase-dead (KR) knock-in mice, immunoprecipitation of CREB-TRPM7 complex, phosphoprotein analysis Scientific reports High 29273814
2018 TRPM7 channel and kinase both contribute to antigen gathering and BCR signaling in B cells; TRPM7-deficient or kinase-deficient DT40 B cells show defective antigen gathering, prolonged BCR signaling, and altered lipid metabolism; blocking TRPM7 function impairs antigen internalization and presentation to T cells. TRPM7-/- and kinase-dead B cell lines, BCR signaling assays, antigen internalization and presentation assays, lipid metabolism analysis Science signaling High 29871912
2018 TRPM7 ion channel activity (not kinase activity) is required for B cell development; mice lacking TRPM7 in B cells exhibit developmental block at the pro-B cell stage; high extracellular Mg2+ partially rescues TRPM7-deficient B cell development in vitro. B cell-specific TRPM7 knockout mice, flow cytometry of B cell developmental stages, Mg2+ rescue experiments in vitro Science signaling High 29871911
2019 TRPM7 signaling regulates RhoA activity and actin polymerization, MRTF-A–Filamin A complex formation, and MRTF-A/SRF-dependent gene expression through Mg2+ influx via the channel and phosphorylation of RhoA by TRPM7 kinase. TRPM7 pharmacological inhibition (NS8593), CRISPR knockout, RhoA activity assays, actin polymerization assays, co-immunoprecipitation of MRTF-A/Filamin A Oncogene High 31844251
2021 Native TRPM7 channels in rodent brain form high-molecular-weight multi-protein complexes containing CNNM1-4 metal transporter proteins and the small GTPase ARL15; reconstitution experiments confirm TRPM7/CNNM/ARL15 ternary complex formation, which specifically impacts TRPM7 channel activity. Multi-epitope affinity purification from native brain tissue, quantitative mass spectrometry, heterologous reconstitution, patch-clamp electrophysiology eLife High 34766907
2021 CNNM proteins selectively bind to and stimulate TRPM7 channel-mediated divalent cation entry; CNNMs require the TRPM7 channel pore for divalent uptake; PRL phosphatases stimulate TRPM7-dependent divalent entry via CNNMs; CNNMs also possess separate TRPM7-independent Mg2+ efflux activity. CNNM knockouts in HEK-293 cells, pore-dead TRPM7 mutants, whole-cell patch-clamp, divalent cation uptake assays, co-expression studies PLoS biology High 34928937
2021 TRPM7 kinase cleaved fragments (M7CKs) accumulate in macrophage nuclei upon Mg2+ stimulation and phosphorylate Histone H3 at serine 10 at promoters of inflammatory cytokines, creating a pro-osteogenic immune microenvironment. Nuclear fractionation, ChIP, TRPM7-dependent H3S10 phosphorylation assays, macrophage Mg2+ influx measurements Nature communications High 34001887
2021 TRPM7 kinase activity regulates neutrophil transmigration along CXCL8 gradient and ROS production in response to LPS; TRPM7 kinase affects Akt1/mTOR signaling in neutrophils, controlling transmigration and effector function. Pharmacological TRPM7 channel and kinase inhibitors, murine neutrophils with genetic kinase ablation, transwell migration assay, ROS production assay, Akt/mTOR signaling analysis Frontiers in immunology High 33658993
2022 Intracellular Mg2+ binds to a conserved N1097 inter-subunit site in the lower channel gate of TRPM7, stabilizing the closed state; removal of Mg2+ from this site favors channel opening, establishing the structural mechanism of Mg2+-dependent TRPM7 inhibition. Site-directed mutagenesis, whole-cell and single-channel patch-clamp, molecular dynamics simulations Cellular and molecular life sciences High 35389104
2022 TRPM7 is required for phagosome maturation during efferocytosis in macrophages; TRPM7 mediates a pH-activated cationic current that sustains phagosomal acidification; TRPM7-dependent peri-phagosomal Ca2+ signals are necessary for phagosome maturation. siRNA screen, perforated patch electrophysiology, genetically-encoded Ca2+ sensor in mice, phagosome acidification and cargo digestion assays Nature communications High 35680919
2022 TrpM7 is palmitoylated at a cysteine cluster at the C-terminal end of its Trp domain by zDHHC17 (Golgi) and zDHHC5 (surface membrane); palmitoylation controls TrpM7 exit from the ER and distribution between cell surface and intracellular vesicles; non-palmitoylated TrpM7 is sequestered intracellularly and shows significantly reduced transmembrane Ca2+ uptake. RUSH trafficking system, palmitoylation site mutagenesis, zDHHC knockdown/identification, Ca2+ uptake assay Cell calcium High 36027648
2022 A TRPM7 gain-of-function mutation (A931T) in transmembrane domain S3 generates an omega current carried by Na+ that is insensitive to the pore blocker Gd3+; expression of A931T in trigeminal ganglion neurons lowers current threshold, resting membrane potential, and increases evoked firing, suggesting this mutation underlies pain in familial trigeminal neuralgia. Whole-exome sequencing, patch-clamp analysis of mutant channels, Na+/Ca2+ imaging, transfection of TG neurons with A931T Proceedings of the National Academy of Sciences High 36095216
2023 Cryo-EM structures of TRPM7 reveal two distinct activation mechanisms: gain-of-function mutation and the agonist naltriben show different conformational dynamics and domain involvement; a binding site for potent selective inhibitors was identified in the closed state; inhibitors act by stabilizing the TRPM7 closed state. Cryo-EM structure determination, functional mutagenesis, molecular dynamics simulations, electrophysiology Nature communications High 37156763
2023 TRPM7 channel transcriptionally regulates glycolytic enzyme SLC2A3/GLUT3 via Ca2+ influx-induced calcineurin activation, acting through CRTC2 and CREB as downstream effectors; TRPM7 deletion suppresses cancer cell glycolysis and xenograft tumor growth, and inhibits postnatal retinal angiogenesis. RNA-seq, metabolomics, TRPM7 knockout cells and mice, calcineurin inhibition, CRTC2/CREB rescue experiments, in vivo tumor and retinal angiogenesis models Cell death & disease High 36878949
2023 PRL-1/2 phosphatases enhance TRPM7 Mg2+ channel activity by preventing CNNM3 interaction with TRPM7; ARL15 (small GTPase) increases CNNM3/TRPM7 complex formation to reduce TRPM7 activity; at low cellular Mg2+, CNNM3-TRPM7 interaction is reduced in a PRL-dependent manner, coupling Mg2+ sensing to TRPM7 function. Genetically-encoded intracellular Mg2+ reporter, co-immunoprecipitation, TRPM7 activity assays, PRL-1/2 KO cells Proceedings of the National Academy of Sciences High 36972446
2014 TRPM6 kinase cross-phosphorylates TRPM7 on serine residues (but not vice versa), alters TRPM7 intracellular trafficking, and inhibits TRPM7-dependent cell growth under hypomagnesic conditions in a kinase-activity-dependent manner. Kinase phosphorylation assays, TRPM7 trafficking analysis in HEK-293 and DT40 cells, kinase-dead TRPM6 mutant complementation, cell growth assays Cellular and molecular life sciences High 24858416
2021 TRPM7 channel stimulation by clozapine or naltriben mediates Zn2+ release from intracellular Zn2+-accumulating vesicles (where TRPM7 localizes) into the cytosol; this Zn2+ release disrupts autophagosome-lysosome fusion by interfering with Sxt17-VAMP8 interaction, arresting autophagy. Zn2+ imaging, TRPM7 pharmacological activation, co-immunoprecipitation of Sxt17-VAMP8, autophagy flux assays, intracellular TRPM7 localization Cancer letters Medium 34752845
2020 TRPM7 kinase deficiency (TRPM7+/Δkinase mice) causes cardiac hypertrophy, fibrosis, and inflammation; reduced cardiac Mg2+ (not Ca2+), upregulation of calpain, and increased pro-fibrotic cytokine signaling (SMAD3, TGFβ) are downstream consequences; TRPM7+/Δkinase macrophages drive cardiac fibroblast activation. TRPM7 kinase-deficient mice, cardiac histology, cytokine profiling, macrophage-fibroblast co-culture, intracellular ion measurements, intra-vital microscopy Cardiovascular research High 31250885

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 807 11385574
2006 Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. The Journal of general physiology 318 16636202
2006 TRPM7, a novel regulator of actomyosin contractility and cell adhesion. The EMBO journal 297 16407977
2009 Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nature neuroscience 240 19734892
2021 TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nature communications 231 34001887
2007 TRPM6 and TRPM7--Gatekeepers of human magnesium metabolism. Biochimica et biophysica acta 209 17481860
2004 Phosphorylation of annexin I by TRPM7 channel-kinase. The Journal of biological chemistry 173 15485879
2014 The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase. Cell 155 24855944
2019 TRPM7, Magnesium, and Signaling. International journal of molecular sciences 128 30995736
2015 Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion. Oncotarget 116 25965832
2014 TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways. Cellular signalling 99 25192910
2017 The TRPM7 channel kinase regulates store-operated calcium entry. The Journal of physiology 96 28130783
2014 TRPM7. Handbook of experimental pharmacology 91 24756720
2020 Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis. Cardiovascular research 90 31250885
2022 TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis. Redox biology 87 35917680
2008 Downregulation of renal TRPM7 and increased inflammation and fibrosis in aldosterone-infused mice: effects of magnesium. Hypertension (Dallas, Tex. : 1979) 85 18268139
2014 TRPM7 regulates proliferation and polarisation of macrophages. Journal of cell science 81 25205764
2014 Activation of TRPM7 channels by small molecules under physiological conditions. Pflugers Archiv : European journal of physiology 80 24633576
2007 The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handbook of experimental pharmacology 77 17217066
2019 Astragaloside IV inhibits cardiac fibrosis via miR-135a-TRPM7-TGF-β/Smads pathway. Journal of ethnopharmacology 76 31739105
2017 Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target. Pharmaceuticals (Basel, Switzerland) 75 28379203
2022 A pan-cancer-bioinformatic-based literature review of TRPM7 in cancers. Pharmacology & therapeutics 73 36332746
2014 Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. Biochimica et biophysica acta 72 24769209
2022 TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation. Journal of experimental & clinical cancer research : CR 70 35101076
2011 TRPM7 regulates polarized cell movements. The Biochemical journal 70 21208190
2007 TRPM7 and TRPM2-Candidate susceptibility genes for Western Pacific ALS and PD? Biochimica et biophysica acta 70 17395433
2011 TRPM7, the Mg(2+) inhibited channel and kinase. Advances in experimental medicine and biology 68 21290295
2010 Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. PloS one 65 20567598
2011 TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions. Current pharmaceutical biotechnology 64 20932259
2016 Decreased TRPM7 inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway. Oncotarget 61 27662662
2010 Transient receptor potential melastatin 7 (TRPM7) cation channels, magnesium and the vascular system in hypertension. Circulation journal : official journal of the Japanese Circulation Society 61 21150127
2013 TRPM7 triggers Ca2+ sparks and invadosome formation in neuroblastoma cells. Cell calcium 60 24176224
2023 Structural mechanisms of TRPM7 activation and inhibition. Nature communications 57 37156763
2014 TRPM7 Regulates Axonal Outgrowth and Maturation of Primary Hippocampal Neurons. Molecular neurobiology 57 25502295
2019 miR-543 inhibites cervical cancer growth and metastasis by targeting TRPM7. Chemico-biological interactions 55 30710498
2017 TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice. Arteriosclerosis, thrombosis, and vascular biology 55 29146750
2018 The Channel-Kinase TRPM7 as Novel Regulator of Immune System Homeostasis. Cells 53 30126133
2014 Natural and Synthetic Modulators of the TRPM7 Channel. Cells 53 25437439
2014 TRPM7 is required for ovarian cancer cell growth, migration and invasion. Biochemical and biophysical research communications 49 25450691
2007 Electroacupuncture regulates TRPM7 expression through the trkA/PI3K pathway after cerebral ischemia-reperfusion in rats. Life sciences 48 17904584
2014 Cellular and Developmental Biology of TRPM7 Channel-Kinase: Implicated Roles in Cancer. Cells 46 25079291
2021 Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway. European journal of pharmacology 44 33647257
2017 Activation of TRPM7 by naltriben enhances migration and invasion of glioblastoma cells. Oncotarget 44 28061441
2011 TRPM7 in cerebral ischemia and potential target for drug development in stroke. Acta pharmacologica Sinica 44 21552293
2021 The molecular appearance of native TRPM7 channel complexes identified by high-resolution proteomics. eLife 43 34766907
2020 Carvacrol affects breast cancer cells through TRPM7 mediated cell cycle regulation. Life sciences 42 33310045
2012 TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets. Scientifica 42 24278689
2019 Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity. Oncogene 41 31844251
2017 Lidocaine suppresses glioma cell proliferation by inhibiting TRPM7 channels. International journal of physiology, pathophysiology and pharmacology 41 28533887
2017 Assessment of TRPM7 functions by drug-like small molecules. Cell calcium 40 28356194
2014 The Pathophysiologic Roles of TRPM7 Channel. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 40 24634592
2014 TRPM7 regulates vascular endothelial cell adhesion and tube formation. American journal of physiology. Cell physiology 40 25472964
2005 TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors. Pflugers Archiv : European journal of physiology 40 16001276
2016 TRPM7 kinase activity regulates murine mast cell degranulation. The Journal of physiology 39 26660477
2016 Bradykinin promotes migration and invasion of hepatocellular carcinoma cells through TRPM7 and MMP2. Experimental cell research 39 27693494
2013 From magnesium to magnesium transporters in cancer: TRPM7, a novel signature in tumour development. Magnesium research 38 24556627
2023 The TRPM7 channel reprograms cellular glycolysis to drive tumorigenesis and angiogenesis. Cell death & disease 35 36878949
2021 CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. PLoS biology 35 34928937
2017 TRPM7 is overexpressed in bladder cancer and promotes proliferation, migration, invasion and tumor growth. Oncology reports 34 28791418
2020 TRPM7/RPSA Complex Regulates Pancreatic Cancer Cell Migration. Frontiers in cell and developmental biology 33 32733880
2005 Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes. Naunyn-Schmiedeberg's archives of pharmacology 33 15902429
2022 Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity. Nature communications 32 35680919
2021 Role of TRPM7 kinase in cancer. Cell calcium 32 33784560
2014 Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity. CNS neuroscience & therapeutics 31 25169754
2013 TRPM7 is regulated by halides through its kinase domain. Cellular and molecular life sciences : CMLS 31 23471296
2020 TRPM7 is overexpressed in human IBD-related and sporadic colorectal cancer and correlates with tumor grade. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 28 32505565
2018 TRPM7 Is Required for Normal Synapse Density, Learning, and Memory at Different Developmental Stages. Cell reports 28 29924992
2019 Role of the chanzyme TRPM7 in the nervous system in health and disease. Cellular and molecular life sciences : CMLS 27 31073743
2017 Role of TRPM7 in cerebral ischaemia and hypoxia. The Journal of physiology 27 27891609
2021 TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling. Frontiers in immunology 26 33658993
2020 Mapping TRPM7 Function by NS8593. International journal of molecular sciences 26 32977698
2022 Structural mechanism of TRPM7 channel regulation by intracellular magnesium. Cellular and molecular life sciences : CMLS 25 35389104
2014 TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions. Cellular and molecular life sciences : CMLS 25 24858416
2020 TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma. Frontiers in pharmacology 24 33381038
2018 The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells. Science signaling 24 29871912
2017 The crucial role of the TRPM7 kinase domain in the early stage of amelogenesis. Scientific reports 24 29273814
2021 Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy. Cancer letters 23 34752845
2020 Suppression of TRPM7 enhances TRAIL-induced apoptosis in triple-negative breast cancer cells. Journal of cellular physiology 23 32468675
2022 A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons. Proceedings of the National Academy of Sciences of the United States of America 22 36095216
2021 TRPM7 Ion Channel: Oncogenic Roles and Therapeutic Potential in Breast Cancer. Cancers 22 34944940
2020 Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions. Cell calcium 22 33080445
2019 TRPM7 deficiency suppresses cell proliferation, migration, and invasion in human colorectal cancer via regulation of epithelial-mesenchymal transition. Cancer biomarkers : section A of Disease markers 22 31640089
2016 The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity. Scientific reports 22 27628598
2022 TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt. Communications biology 21 35882956
2022 Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7. Cell calcium 21 36027648
2022 Pharmacological agents selectively acting on the channel moieties of TRPM6 and TRPM7. Cell calcium 21 36030694
2019 TRPM7 channel inhibition exacerbates pulmonary arterial hypertension through MEK/ERK pathway. Aging 21 31219801
2019 TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia. Laboratory investigation; a journal of technical methods and pathology 21 31444399
2018 The ion channel TRPM7 is required for B cell lymphopoiesis. Science signaling 21 29871911
2015 Novel insights into TRPM7 function in fibrotic diseases: a potential therapeutic target. Journal of cellular physiology 21 25204892
2015 The Different Roles of The Channel-Kinases TRPM6 and TRPM7. Current medicinal chemistry 21 26179995
2023 Adipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice. Nature communications 20 36717580
2021 Tumor suppressor miR-192-5p targets TRPM7 and inhibits proliferation and invasion in cervical cancer. The Kaohsiung journal of medical sciences 20 34042256
2021 Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases. Immunology 20 34558663
2023 PRL-1/2 phosphatases control TRPM7 magnesium-dependent function to regulate cellular bioenergetics. Proceedings of the National Academy of Sciences of the United States of America 19 36972446
2020 Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead. Acta pharmacologica Sinica 19 32994545
2019 Roles of TRPM7 in Renal Ischemia-Reperfusion Injury. Current protein & peptide science 19 31060485
2012 TRPM7, the cytoskeleton and neuronal death. Channels (Austin, Tex.) 19 23247582
2020 A bibliometric analysis and review of recent researches on TRPM7. Channels (Austin, Tex.) 17 32643506
2016 Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7). The Journal of biological chemistry 17 27466368