Affinage

TRPM7

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

Length
1865 aa
Mass
212.7 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM7 is a ubiquitously required bifunctional 'chanzyme' that couples a divalent-cation-permeable ion channel to a C-terminal alpha-kinase domain, integrating cellular Mg2+, Ca2+, and Zn2+ fluxes with cytoskeletal, immune, metabolic, and gene-regulatory programs (PMID:11385574, PMID:11161216). The channel conducts Ca2+ and Mg2+ and is gated by intracellular Mg2+ binding to an inter-subunit N1097 site in the lower gate that stabilizes the closed state (PMID:11385574, PMID:35389104), and is further inhibited by Mg·ATP/GTP and by PIP2 depletion downstream of PLC, whose C2 domain associates directly with the TRPM7 kinase domain (PMID:11385574, PMID:11941371). The kinase autophosphorylates and phosphorylates serine/threonine substrates including myelin basic protein, histone H3, and the myosin IIA heavy chain, requiring Mg2+/Mn2+ as cofactor (PMID:14594813, PMID:16407977); its catalytic activity is dispensable for ion conduction, but the kinase domain is structurally required for channel assembly (PMID:15781465). Through channel-mediated Mg2+ influx and kinase-dependent phosphorylation (including RhoA), TRPM7 controls actomyosin contractility, Rac/Cdc42 and MRTF-A/SRF signaling, lamellipodia formation, cell adhesion, and migration (PMID:16407977, PMID:21208190, PMID:31844251). Genetic dissection in mice and DT40 cells separates channel-dependent functions—B cell lymphopoiesis, store refilling, phagosomal acidification during efferocytosis, and endosomal acidification supporting V-ATPase-driven pH for enveloped-virus entry—from kinase-dependent functions such as mast cell degranulation, SMAD2-controlled T cell gut-homing, platelet PLC signaling/thrombosis, and neutrophil transmigration (PMID:29871911, PMID:26660477, PMID:29203869, PMID:29146750, PMID:35680919, PMID:39353909). A nuclear kinase-cleaved fragment phosphorylates histone H3 Ser10 at inflammatory cytokine promoters, and channel-driven Ca2+ activates calcineurin/CRTC2/CREB to reprogram glycolysis (PMID:34001887, PMID:36878949). TRPM7 activity is additionally tuned by zDHHC17/zDHHC5-mediated palmitoylation governing trafficking, by assembly into native TRPM7/CNNM/ARL15 complexes, and by TRPM6 cross-phosphorylation (PMID:34766907, PMID:36027648, PMID:24858416). No timeline discovery links TRPM7 to a defined Mendelian disease via causative mutation.

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    Established that TRPM7 is a divalent cation channel essential for viability and is bifunctional, carrying an integral alpha-kinase whose catalytic site is required for channel function—defining the 'chanzyme' concept.

    Evidence Electrophysiology in HEK/CHO overexpression and native cells, targeted DT-40 deletion (lethal), kinase-active-site mutagenesis and autophosphorylation

    PMID:11161216 PMID:11385574

    Open questions at the time
    • Did not resolve whether kinase catalysis vs domain structure underlies the channel requirement
    • No structural basis for ion selectivity
  2. 2002 High

    Linked TRPM7 gating to receptor-driven lipid signaling by showing the kinase domain binds PLC and that PIP2 hydrolysis inactivates the channel, placing TRPM7 downstream of Gq/RTK pathways.

    Evidence Co-IP of kinase–PLC C2 domain, electrophysiology with receptor stimulation and PIP2 manipulation

    PMID:11941371

    Open questions at the time
    • Stoichiometry of PIP2 binding to the channel not defined
    • Did not separate PIP2 depletion from concurrent Ca2+ changes
  3. 2003 High

    Defined the biochemical properties of the kinase as a Mg2+/Mn2+-dependent, ATP-specific, staurosporine-insensitive serine/threonine enzyme with histone H3 and MBP as substrates.

    Evidence In vitro kinase assay with bacterially expressed kinase domain, substrate and cofactor titrations

    PMID:14594813

    Open questions at the time
    • Physiological substrates not identified at this stage
    • No structure of the active site
  4. 2004 High

    Showed channel activity is bidirectionally controlled by GPCR–cAMP/PKA signaling in a manner requiring the intact kinase domain, connecting TRPM7 to second-messenger tuning.

    Evidence Patch-clamp with Gi/Gs receptor pharmacology, kinase-dead mutants, PKA inhibitors

    PMID:15069188

    Open questions at the time
    • PKA phosphorylation site on TRPM7 not mapped
    • Mechanism of kinase-domain requirement unresolved
  5. 2005 High

    Resolved that kinase catalysis is dispensable for conduction and Mg2+ inhibition while the kinase domain is structurally required, refining the channel–kinase coupling model.

    Evidence Autophosphorylation/catalytic-site mutagenesis, MS phosphosite mapping (Ser1511/Ser1567), patch-clamp and Ca2+ influx

    PMID:15781465

    Open questions at the time
    • How the kinase domain supports assembly/localization not mechanistically defined
    • Function of autophosphorylation sites unknown
  6. 2006 High

    Identified myosin IIA heavy chain as a kinase substrate and connected TRPM7 to actomyosin-dependent adhesion, spreading, and podosome formation via combined kinase-dependent and -independent routes.

    Evidence In vitro myosin IIA phosphorylation, live-cell imaging, Co-IP, myosin II pharmacology

    PMID:16407977

    Open questions at the time
    • Did not quantify in vivo phosphostoichiometry
    • Channel vs kinase contributions to each phenotype not fully separated
  7. 2009 Medium

    Revealed a second feedback inhibition of the channel by cytosolic Ca2+ acting through CaMKII, adding Ca2+ sensing to the established Mg2+ regulation.

    Evidence Whole-cell patch-clamp with CaMKII inhibitor pharmacology and Mg·ATP dialysis in hepatocytes

    PMID:19661151

    Open questions at the time
    • CaMKII phosphorylation site on TRPM7 not mapped
    • Single lab, native-current identity inferred
  8. 2011 Medium

    Demonstrated that TRPM7-supplied Mg2+ is the critical downstream signal for Rac/Cdc42 activation and polarized migration, since SLC41A2 Mg2+ transport rescues the loss.

    Evidence RNAi, Rac/Cdc42 pulldown, wound-healing assay, SLC41A2 rescue

    PMID:21208190

    Open questions at the time
    • Direct link between Mg2+ and GTPase activation not biochemically defined
    • Single lab
  9. 2013 Medium

    Extended channel regulation to halide inhibition through the kinase ATP-binding site and showed TRPM7-dependent MAPK/Src signaling and channel-driven Ca2+ microdomains underlie cancer cell migration/invasion.

    Evidence Patch-clamp halide titration, siRNA with migration/invasion and pathway blotting, TIRF Ca2+ fluorometry with waixenicin-A

    PMID:23353055 PMID:23471296 PMID:24176224

    Open questions at the time
    • No mutagenesis/rescue for the MAPK link
    • Mechanism coupling halide binding to gating not structurally resolved
  10. 2014 High

    Genetic mouse and DT40 models cleanly separated channel from kinase roles: channel-mediated Mg2+ drives pro-B cell lymphopoiesis (Mg2+-rescuable), while TRPM6 cross-phosphorylates TRPM7 to control its trafficking and growth; TRPM7 also organizes growth-cone F-actin/α-actinin-1.

    Evidence Conditional KO and kinase-dead knock-in mice with Mg2+ rescue; kinase cross-phosphorylation assays in DT40; Co-IP/co-localization and shRNA in neurons

    PMID:24858416 PMID:25502295 PMID:29871911

    Open questions at the time
    • Direction and sites of TRPM6→TRPM7 phosphorylation not fully mapped in vivo
    • Growth-cone work single lab
  11. 2016 High

    Established a channel-independent kinase function in mast cell exocytosis, showing the kinase sets sensitivity to intracellular Ca2+ and the degranulation rate.

    Evidence Kinase-dead knock-in vs kinase-deletion mice, degranulation and histamine release assays, GPCR stimulation

    PMID:26660477

    Open questions at the time
    • Kinase substrate in the exocytic machinery not identified
    • Link to Ca2+ sensitivity mechanism unresolved
  12. 2017 High

    Multiple kinase-dead mouse studies tied TRPM7 kinase to immune and hemostatic signaling—SMAD2-controlled T cell gut-homing/Th17 bias, platelet PLC/SOCE and thrombosis, and store refilling—distinguishing kinase from channel contributions to Ca2+ handling.

    Evidence Trpm7 kinase-dead mice; SMAD2 phosphorylation and Th17/Treg assays; platelet Ca2+/phosphoprotein analysis and in vivo thrombosis/stroke; DT40 KO and kinase mutants with CRAC recordings

    PMID:28130783 PMID:29146750 PMID:29203869

    Open questions at the time
    • Direct kinase phosphorylation of SMAD2/PLC substrates not shown in vitro
    • How kinase modulates SOCE mechanistically unresolved
  13. 2018 Medium

    Showed both channel and kinase functions are needed for B cell antigen internalization and lipid metabolism, nominating PLCγ2 as a candidate kinase target.

    Evidence TRPM7-deficient/kinase-dead DT40 B cells, antigen gathering/internalization, BCR signaling and lipid profiling

    PMID:29871912

    Open questions at the time
    • PLCγ2 not validated as direct substrate by in vitro phosphorylation
    • Single lab
  14. 2019 Medium

    Connected TRPM7 to transcriptional control of cell shape and tumor growth via combined Mg2+ influx and kinase-dependent RhoA phosphorylation driving MRTF-A/SRF activity.

    Evidence NS8593 inhibition, genome editing, RhoA activity and actin polymerization assays, MRTF-A imaging, xenografts

    PMID:31250885 PMID:31844251

    Open questions at the time
    • RhoA phosphorylation by TRPM7 kinase not confirmed by direct in vitro assay
    • Cardiac kinase-deletion phenotype mechanism (calpain) correlative
  15. 2021 High

    Identified native TRPM7/CNNM/ARL15 ternary complexes that modulate activity and a nuclear kinase-cleaved fragment that phosphorylates H3S10 at cytokine promoters; channel-released Zn2+ was shown to block autophagosome–lysosome fusion.

    Evidence Affinity purification/quantitative MS from brain with heterologous reconstitution; nuclear fractionation/ChIP in macrophages; agonist-induced Zn2+ imaging and Stx17/VAMP8 Co-IP with xenografts

    PMID:33658993 PMID:34001887 PMID:34752845 PMID:34766907

    Open questions at the time
    • Protease generating the nuclear fragment not identified
    • Functional consequence of CNNM/ARL15 binding on gating not structurally resolved
  16. 2022 High

    Defined structural and trafficking control of TRPM7—N1097 inter-subunit Mg2+ gate, zDHHC17/zDHHC5 palmitoylation governing surface/vesicle distribution—and channel-dependent roles in phagosomal acidification/efferocytosis, chondrocyte ferroptosis, and a gain-of-function A931T 'omega current'.

    Evidence Cryo-EM/MD with mutagenesis; palmitoylation/RUSH trafficking assays; perforated-patch and phagosomal pH/Ca2+ imaging; PKCα-NOX4 Co-IP; A931T mutagenesis in neurons

    PMID:35389104 PMID:35680919 PMID:35917680 PMID:36027648 PMID:36095216

    Open questions at the time
    • Coupling between palmitoylation and gating not mechanistically resolved
    • A931T variant not linked to a defined human disease in the corpus
  17. 2023 Medium

    Defined channel-driven metabolic reprogramming via calcineurin/CRTC2/CREB upregulation of GLUT3, refined CNNM/PRL/ARL15 regulation of Mg2+ transport, and resolved distinct activation/inhibition conformations by cryo-EM.

    Evidence RNA-seq/metabolomics with CRTC2/CREB rescue and xenografts; Mg2+ reporter with CNNM3/PRL/ARL15 Co-IP; cryo-EM with agonist/gain-of-function and inhibitor-bound states

    PMID:36878949 PMID:36972446 PMID:37156763

    Open questions at the time
    • Direct transcriptional target validation limited to single lab
    • Inhibitor binding site not yet exploited therapeutically in the corpus
  18. 2024 High

    Established a broadly protective antiviral role: TRPM7 channel countercurrent sustains V-ATPase-driven endosomal acidification required for entry of multiple low-pH enveloped viruses.

    Evidence TRPM7 KO/KD across pseudovirus and authentic virus systems, endosomal pH measurement, electrophysiology

    PMID:39353909

    Open questions at the time
    • Endosomal vs plasma-membrane channel pool not distinguished
    • Therapeutic exploitation not tested in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the kinase and channel modules are physically and energetically coupled—whether intramolecular phosphorylation, conformational coupling, or complex assembly dictates the division between channel-dependent and kinase-dependent physiology—remains unresolved.
  • No structure capturing kinase–channel allosteric coupling
  • Most physiological kinase substrates inferred rather than shown by direct in vitro phosphorylation
  • No human Mendelian disease established for TRPM7 in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 2 GO:0140657 ATP-dependent activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 1 R-HSA-9612973 Autophagy 1
Partners
ACTN1 (Α-ACTININ-1)ARL15CNNM3MYH9 (MYOSIN IIA)PLCB (PLC)TRPM6ZDHHC17ZDHHC5
Complex memberships
TRPM7/CNNM/ARL15 ternary complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 LTRPC7/TRPM7 is a Ca2+- and Mg2+-permeable divalent cation channel whose activity is regulated by millimolar intracellular Mg·ATP and Mg·GTP; targeted deletion of LTRPC7 in DT-40 B cells was lethal, establishing a nonredundant role in cellular viability. Electrophysiology (whole-cell patch-clamp in HEK-293 overexpression and native cells), targeted gene deletion in DT-40 B cells Nature High 11385574
2001 TRP-PLIK/TRPM7 is a bifunctional protein possessing both an ion channel (nonselective, Ca2+-permeant, 105 pS, outwardly rectifying) and a functional alpha-kinase domain; kinase-dead mutagenesis demonstrated that the kinase activity is essential for channel function. Electrophysiology (CHO-K1 expression), site-directed mutagenesis of kinase active site, autophosphorylation assay Science High 11161216
2002 TRPM7 channel activity is inhibited by PIP2 hydrolysis: the kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC), and Gαq- or tyrosine kinase receptor-mediated PLC activation depletes local PIP2, inactivating the channel. Co-immunoprecipitation (kinase–PLC C2 domain interaction), electrophysiology in native cardiac cells and heterologous systems, receptor stimulation and PIP2 manipulation experiments Nature Cell Biology High 11941371
2003 The TRPM7/ChaK1 alpha-kinase domain expressed in bacteria undergoes autophosphorylation and phosphorylates myelin basic protein and histone H3 on serine/threonine residues; the kinase is ATP-specific, insensitive to staurosporine, inhibited by rottlerin, and requires Mg2+ or Mn2+ as cofactors. In vitro kinase assay with bacterially expressed kinase domain, substrate phosphorylation, cofactor titrations Journal of Biological Chemistry High 14594813
2004 TRPM7 channel activity is bidirectionally regulated through its endogenous kinase domain in a cAMP/PKA-dependent manner: Gi-coupled muscarinic receptors suppress and Gs-coupled beta-adrenergic receptors potentiate TRPM7 currents; both effects require functional PKA and the intact TRPM7 kinase domain. Whole-cell patch-clamp, receptor agonist/antagonist pharmacology, kinase-dead TRPM7 mutants, PKA inhibitors (H89, KT5720) PNAS High 15069188
2005 Autophosphorylation of TRPM7 at Ser1511 and Ser1567 (identified by mass spectrometry) and catalytic activity of the kinase are not required for channel ion conductance or Mg2+ inhibition; however, deletion of the kinase domain abolishes channel activity, indicating a structural role for the kinase domain in channel assembly or localization. Site-directed mutagenesis of autophosphorylation and catalytic sites, mass spectrometry identification of phosphorylation sites, whole-cell patch-clamp, Ca2+ influx assays Journal of Biological Chemistry High 15781465
2006 TRPM7 phosphorylates myosin IIA heavy chain and, upon activation by bradykinin, undergoes a Ca2+- and kinase-dependent interaction with the actomyosin cytoskeleton; TRPM7 regulates cell spreading, adhesion, focal adhesion formation, and podosome induction through combined kinase-dependent and -independent pathways on actomyosin contractility. In vitro kinase assay (myosin IIA heavy chain phosphorylation), live-cell imaging, co-immunoprecipitation, overexpression/pharmacological inhibition of myosin II EMBO Journal High 16407977
2013 Chloride and bromide inhibit TRPM7 channel activity synergistically with intracellular Mg2+ through the ATP-binding site of the kinase domain; iodide exerts the strongest inhibitory effect and can suppress endogenous TRPM7-like currents in MCF-7 breast cancer cells. Whole-cell patch-clamp of heterologously expressed and endogenous TRPM7, pharmacological manipulation of halide concentrations and kinase ATP-binding site Cellular and Molecular Life Sciences Medium 23471296
2011 TRPM7 depletion by RNAi in fibroblasts disrupts lamellipodia formation and polarized cell migration; TRPM7 loss prevents activation of Rac and Cdc42 upon wound stimulation; re-expression of kinase-inactive TRPM7 or the Mg2+ transporter SLC41A2 reverses cytoskeletal and motility defects, indicating Mg2+ as the critical downstream signal. RNA interference, pulldown/GTPase activation assay (Rac/Cdc42), wound-healing assay, SLC41A2 rescue expression Biochemical Journal Medium 21208190
2013 TRPM7 mediates migration and invasion of breast cancer cells via the MAPK pathway; TRPM7 silencing decreases phosphorylation of Src and ERK/MAPK but not AKT. RNA interference (siRNA knockdown), migration/invasion assays, western blotting for pathway phosphorylation Cancer Letters Medium 23353055
2013 TRPM7 promotes localized Ca2+ microdomain ('Ca2+ sparks') at the ventral plasma membrane in a channel-dependent manner; invadosome formation by TRPM7 is spatially and functionally dissociated from TRPM7-mediated Ca2+ sparks and instead depends on effects on actomyosin contractility. TIRF Ca2+ fluorometry, TRPM7 channel inhibitor (waixenicin-A), knockdown, live-cell imaging Cell Calcium Medium 24176224
2014 TRPM7 channel activity is required for B cell lymphopoiesis at the pro-B cell stage in mice; loss of kinase activity alone does not impair B cell development; high extracellular Mg2+ partially rescues TRPM7-deficient B cell development in vitro, indicating an ion channel (Mg2+) function is critical. Conditional B cell-specific TRPM7 knockout mice, kinase-dead knock-in mice, in vitro rescue with Mg2+ supplementation, flow cytometry Science Signaling High 29871911
2016 TRPM7 kinase activity regulates mast cell degranulation and histamine release independently of TRPM7 channel function; impaired TRPM7 kinase decreases sensitivity to intracellular Ca2+ in G protein-induced exocytosis and slows the cellular degranulation rate. Mast cell degranulation assays, histamine release measurement, TRPM7 kinase-dead knock-in mice (TRPM7KR) vs kinase-deletion mice (TRPM7+/ΔK), GPCR stimulation experiments Journal of Physiology High 26660477
2017 TRPM7 kinase activity controls TGF-β-induced CD103 expression and gut-homing of intraepithelial T lymphocytes by modulating SMAD2 phosphorylation; TRPM7 kinase promotes pro-inflammatory Th17 but not regulatory T cell differentiation. TRPM7 kinase-dead mutant mice (Trpm7 R/R), T cell gut colonization assays, SMAD2 phosphorylation analysis, Th17/Treg differentiation experiments Nature Communications High 29203869
2017 TRPM7 kinase activity modulates PLC signaling (phosphorylation of Syk, PLCγ2 and PLCβ3) and store-operated Ca2+ entry in platelets; platelets from Trpm7 kinase-dead mice show impaired PIP2 metabolism and reduced Ca2+ mobilization in response to GPVI, CLEC-2, and PAR receptors, protecting mice from arterial thrombosis and ischemic stroke. Trpm7 kinase-dead knock-in mice, platelet Ca2+ mobilization assays, phosphoprotein western blotting, in vivo arterial thrombosis and stroke models Arteriosclerosis, Thrombosis, and Vascular Biology High 29146750
2017 TRPM7 kinase rather than channel activity modulates store-operated Ca2+ entry (SOCE); TRPM7 channel activity maintains resting ER Ca2+ levels and supports store refilling after Ca2+ signaling events, but TRPM7 is not itself a store-operated Ca2+ channel. TRPM7−/− DT40 B cells, kinase-deficient mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ flux measurements, CRAC current recordings Journal of Physiology High 28130783
2018 TRPM7 channel and kinase functions are both required for antigen gathering and internalization in B cells; TRPM7 deficiency or kinase-dead mutation impairs lipid metabolism and results in defective BCR signaling, and PLCγ2 is a putative target of TRPM7 kinase activity. TRPM7-deficient DT40 B cells, kinase-deficient mutant, antigen gathering/internalization assays, BCR signaling analysis, lipid metabolism profiling Science Signaling Medium 29871912
2019 TRPM7 kinase activity controls RhoA phosphorylation and downstream actin polymerization, leading to MRTF-A/SRF-dependent transcriptional activity; TRPM7 channel-mediated Mg2+ influx and TRPM7 kinase-mediated RhoA phosphorylation together regulate MRTF-A nuclear localization and HCC tumor growth. Pharmacological TRPM7 inhibition (NS8593), genome editing, RhoA activity assay, actin polymerization assay, MRTF-A localization imaging, xenograft models Oncogene Medium 31844251
2021 Native TRPM7 channels in rodent brain exist as high-molecular-weight multi-protein complexes containing CNNM1-4 metal transporter proteins and the small GTPase ARL15; heterologous reconstitution confirmed TRPM7/CNNM/ARL15 ternary complex formation that effectively and specifically modulates TRPM7 activity. Multi-epitope affinity purification, high-resolution quantitative mass spectrometry, heterologous reconstitution co-immunoprecipitation, functional TRPM7 activity assays eLife High 34766907
2021 TRPM7 kinase-cleaved fragments (M7CKs) accumulate in the nucleus and phosphorylate histone H3 at serine 10 at the promoters of inflammatory cytokines in macrophages, triggering a pro-osteogenic immune microenvironment in response to Mg2+ influx. TRPM7 kinase fragment nuclear localization (fractionation/imaging), chromatin immunoprecipitation (H3S10 phosphorylation at cytokine promoters), TRPM7-dependent Mg2+ influx assays Nature Communications Medium 34001887
2021 TRPM7 kinase is essential for neutrophil transmigration along a CXCL8 gradient and for ROS production in response to LPS; TRPM7 kinase activity regulates Akt1/mTOR signaling in neutrophils. Pharmacological TRPM7 channel and kinase inhibition (TG100-115), murine neutrophils with genetic kinase ablation, transmigration assay, ROS measurement, Akt1/mTOR phosphorylation western blotting Frontiers in Immunology Medium 33658993
2022 TRPM7 mediates a pH-activated cationic current essential for phagosomal acidification and maturation during macrophage efferocytosis; TRPM7 is required for peri-phagosomal Ca2+ signals and digestion of apoptotic cell cargo. siRNA screen, perforated-patch electrophysiology, phagosomal pH measurements, genetically-encoded Ca2+ sensors in mice Nature Communications High 35680919
2022 TRPM7 is palmitoylated at a cluster of cysteines at the C-terminal end of its Trp domain by Golgi-resident zDHHC17 and surface membrane-resident zDHHC5; palmitoylation controls TRPM7 exit from the ER and distribution between cell surface and intracellular vesicles, and non-palmitoylated TRPM7 has significantly reduced transmembrane Ca2+ uptake. Palmitoylation assay, RUSH trafficking system (live imaging), zDHHC enzyme identification (co-expression/knockdown), Ca2+ flux measurement with non-palmitoylatable mutants Cell Calcium High 36027648
2022 Structural analysis by cryo-EM and MD simulations identified N1097 as forming an inter-subunit Mg2+ regulatory site in the lower gate of TRPM7; intracellular Mg2+ binds this site to stabilize the closed state, and its removal favors channel opening. Site-directed mutagenesis, whole-cell and single-channel patch-clamp, molecular dynamics simulations Cellular and Molecular Life Sciences High 35389104
2023 Cryo-EM structures of TRPM7 revealed two distinct mechanisms of channel activation: a gain-of-function mutation and the agonist naltriben show different conformational dynamics and domain involvement; a binding site for potent selective inhibitors was identified and shown to stabilize the closed state. Cryo-EM structure determination, functional electrophysiology, molecular dynamics simulations, inhibitor binding site mapping Nature Communications High 37156763
2023 TRPM7 transcriptionally upregulates the glucose transporter SLC2A3/GLUT3 via Ca2+ influx-induced calcineurin activation and downstream CRTC2/CREB signaling, reprogramming cellular glycolysis to drive tumorigenesis and angiogenesis; constitutively active CRTC2 or CREB normalized glycolysis in TRPM7 knockout cells. RNA-seq, metabolomics, TRPM7 genetic deletion, rescue with constitutively active CRTC2/CREB, Ca2+ imaging, xenograft models Cell Death & Disease Medium 36878949
2023 PRL-1/2 phosphatases promote TRPM7 function by preventing CNNM3 interaction with TRPM7, while ARL15 increases CNNM3/TRPM7 complex formation to reduce TRPM7 activity; CNNM family proteins inhibit TRPM7 magnesium channel function, and co-targeting TRPM7 and PRL-1/2 sensitizes cells to metabolic stress under Mg2+ depletion. Genetically encoded Mg2+ reporter, co-immunoprecipitation (CNNM3/TRPM7/ARL15 complex), PRL-2 overexpression/knockdown, functional Mg2+ transport assays PNAS Medium 36972446
2014 TRPM6 kinase cross-phosphorylates TRPM7 on serine residues (but TRPM7 does not phosphorylate TRPM6 on serine), alters TRPM7 intracellular trafficking, and inhibits TRPM7-dependent cell growth under hypomagnesic conditions in a TRPM6 kinase-dependent manner. Kinase cross-phosphorylation assays, intracellular trafficking experiments, DT40 TRPM7-deficient complementation, surface labeling, TRPM6 kinase-dead mutant co-expression Cellular and Molecular Life Sciences Medium 24858416
2022 TRPM7 channel activity contributes to chondrocyte ferroptosis by elevating intracellular Ca2+; mechanistically, the PKCα-NOX4 axis responds to erastin stimulation in a TRPM7-dependent manner, with PKCα directly binding NOX4 in a manner reduced by TRPM7 channel inhibition. TRPM7 knockdown and pharmacological inhibition, PKCα-NOX4 co-immunoprecipitation, Ca2+ imaging, AAV9-mediated TRPM7 silencing in vivo, ferroptosis assays Redox Biology Medium 35917680
2024 TRPM7 ion channel activity is required for endosomal acidification of virus-laden endosomes by providing a countercurrent of cations from the endosomal lumen to the cytosol, thereby sustaining V-ATPase-driven proton pumping; loss of TRPM7 protects cells from infection by multiple low-pH-requiring enveloped viruses (Lassa, LCMV, Ebola, Influenza, MERS, SARS-CoV-1, SARS-CoV-2) without affecting other endosomal acidification pathways. TRPM7 knockout/knockdown, multiple viral infection systems (pseudovirus and authentic virus), endosomal pH measurements, electrophysiology of TRPM7 currents Nature Communications High 39353909
2014 TRPM7 co-precipitates and co-localizes with F-actin and α-actinin-1 at neuronal growth cones; Ca2+ influx through TRPM7 inhibits axonal outgrowth and maturation by regulating the F-actin/α-actinin-1 protein complex. Co-immunoprecipitation, immunofluorescence co-localization, TRPM7 shRNA knockdown, pharmacological channel block (waixenicin A), Ca2+ imaging, neurite outgrowth assay Molecular Neurobiology Medium 25502295
2022 A gain-of-function TRPM7 variant (A931T) in the S3 transmembrane segment generates an anomalous 'omega current' carried by Na+ and insensitive to the pore blocker Gd3+; alanine substitutions of F971 and W972 implicated an A931-W972 hydrophobic interaction in S3-S4 cleft stability; expression of A931T in trigeminal ganglion neurons lowered firing threshold and increased evoked activity. Patch-clamp analysis, Ca2+ and Na+ imaging, site-directed mutagenesis (A931T, F971A, W972A), transfection of trigeminal ganglion neurons PNAS Medium 36095216
2021 TRPM7 channel activation by clozapine or naltriben mobilizes Zn2+ from intracellular TRPM7-localized vesicles into the cytosol, disrupting the interaction between Sxt17 and VAMP8 and blocking autophagosome-lysosome fusion, thereby arresting autophagy. TRPM7 agonist treatment (clozapine, naltriben), Zn2+ imaging, autophagosome-lysosome fusion assay, co-immunoprecipitation (Sxt17/VAMP8), in vivo xenograft models Cancer Letters Medium 34752845
2020 TRPM7 kinase deficiency in mice (TRPM7+/Δkinase) causes cardiac hypertrophy, fibrosis, and inflammation with reduced intracellular Mg2+; calpain (a downstream TRPM7 target) is upregulated and activated; TRPM7+/Δkinase macrophages increase fibronectin, PCNA, and TGFβ in cardiac fibroblasts in a Mg2+-reversible manner. TRPM7 kinase-deletion mice, cardiac histology, macrophage-fibroblast co-culture, calpain activity assay, intravital microscopy Cardiovascular Research Medium 31250885
2009 Hepatocellular TRPM7-like channels are inhibited by cytosolic Ca2+ in a CaMKII-dependent manner (IC50 ~125 nM), in addition to their established Mg2+ sensitivity; CaMKII inhibitors partially relieve Ca2+-dependent channel inhibition. Whole-cell patch-clamp, CaMKII inhibitor pharmacology (W-7, staurosporine, KN-93, CaMKII inhibitory peptide), Mg2+/Mg-ATP dialysis American Journal of Physiology – Gastrointestinal and Liver Physiology Medium 19661151
2020 TRPM7 channel-mediated Mg2+ influx and TRPM7 kinase-mediated phosphorylation of RhoA together regulate actin dynamics and MRTF-A nuclear localization; Mg2+ influx and RhoA phosphorylation are both required for MRTF-A/SRF transcriptional activity in hepatocellular carcinoma cells. Pharmacological TRPM7 inhibition (NS8593), targeted genome editing, RhoA activity assay, MRTF-A nuclear localization imaging, actin polymerization assay Oncogene Medium 31844251

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 810 11385574
2001 TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science (New York, N.Y.) 616 11161216
2002 The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nature cell biology 428 11941371
2006 TRPM7, a novel regulator of actomyosin contractility and cell adhesion. The EMBO journal 299 16407977
2021 TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration. Nature communications 245 34001887
2007 TRPM6 and TRPM7--Gatekeepers of human magnesium metabolism. Biochimica et biophysica acta 211 17481860
2003 Characterization of the protein kinase activity of TRPM7/ChaK1, a protein kinase fused to the transient receptor potential ion channel. The Journal of biological chemistry 164 14594813
2005 Channel function is dissociated from the intrinsic kinase activity and autophosphorylation of TRPM7/ChaK1. The Journal of biological chemistry 161 15781465
2004 Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain. Proceedings of the National Academy of Sciences of the United States of America 147 15069188
2019 TRPM7, Magnesium, and Signaling. International journal of molecular sciences 131 30995736
2013 TRPM7 mediates breast cancer cell migration and invasion through the MAPK pathway. Cancer letters 128 23353055
2015 Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion. Oncotarget 117 25965832
2014 TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways. Cellular signalling 100 25192910
2017 The TRPM7 channel kinase regulates store-operated calcium entry. The Journal of physiology 96 28130783
2014 TRPM7. Handbook of experimental pharmacology 95 24756720
2020 Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis. Cardiovascular research 93 31250885
2022 TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis. Redox biology 88 35917680
2017 TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut. Nature communications 87 29203869
2014 TRPM7 regulates proliferation and polarisation of macrophages. Journal of cell science 83 25205764
2007 The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handbook of experimental pharmacology 78 17217066
2017 Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target. Pharmaceuticals (Basel, Switzerland) 76 28379203
2022 A pan-cancer-bioinformatic-based literature review of TRPM7 in cancers. Pharmacology & therapeutics 74 36332746
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 73 35101076
2014 Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. Biochimica et biophysica acta 72 24769209
2011 TRPM7, the Mg(2+) inhibited channel and kinase. Advances in experimental medicine and biology 71 21290295
2014 Function and regulation of the channel-kinase TRPM7 in health and disease. European journal of cell biology 70 25073440
2012 TRPM7: a unique channel involved in magnesium homeostasis. The international journal of biochemistry & cell biology 70 22634382
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
2015 TRPM7 and its role in neurodegenerative diseases. Channels (Austin, Tex.) 69 26218331
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 59 37156763
2017 TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice. Arteriosclerosis, thrombosis, and vascular biology 58 29146750
2014 TRPM7 Regulates Axonal Outgrowth and Maturation of Primary Hippocampal Neurons. Molecular neurobiology 58 25502295
2005 TRPM7 and ischemic CNS injury. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 58 15746380
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
2017 Activation of TRPM7 by naltriben enhances migration and invasion of glioblastoma cells. Oncotarget 45 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
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
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 41 24634592
2014 TRPM7 regulates vascular endothelial cell adhesion and tube formation. American journal of physiology. Cell physiology 41 25472964
2017 Assessment of TRPM7 functions by drug-like small molecules. Cell calcium 40 28356194
2016 TRPM7 kinase activity regulates murine mast cell degranulation. The Journal of physiology 40 26660477
2005 TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors. Pflugers Archiv : European journal of physiology 40 16001276
2018 TRPM7 Mediates Mechanosensitivity in Adult Rat Odontoblasts. Journal of dental research 39 29489440
2023 The TRPM7 channel reprograms cellular glycolysis to drive tumorigenesis and angiogenesis. Cell death & disease 37 36878949
2009 Mg2+- and MgATP-inhibited and Ca2+/calmodulin-sensitive TRPM7-like current in hepatoma and hepatocytes. American journal of physiology. Gastrointestinal and liver physiology 36 19661151
2022 Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity. Nature communications 34 35680919
2021 Role of TRPM7 kinase in cancer. Cell calcium 33 33784560
2020 TRPM7/RPSA Complex Regulates Pancreatic Cancer Cell Migration. Frontiers in cell and developmental biology 33 32733880
2013 TRPM7 is regulated by halides through its kinase domain. Cellular and molecular life sciences : CMLS 32 23471296
2014 Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity. CNS neuroscience & therapeutics 31 25169754
2020 TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells. Biochemical and biophysical research communications 30 33153718
2021 TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling. Frontiers in immunology 29 33658993
2019 Role of the chanzyme TRPM7 in the nervous system in health and disease. Cellular and molecular life sciences : CMLS 29 31073743
2017 Role of TRPM7 in cerebral ischaemia and hypoxia. The Journal of physiology 29 27891609
2021 Cell death modulation by transient receptor potential melastatin channels TRPM2 and TRPM7 and their underlying molecular mechanisms. Biochemical pharmacology 28 34175300
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
2020 TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma. Frontiers in pharmacology 27 33381038
2022 Structural mechanism of TRPM7 channel regulation by intracellular magnesium. Cellular and molecular life sciences : CMLS 26 35389104
2020 Mapping TRPM7 Function by NS8593. International journal of molecular sciences 26 32977698
2020 TRPM7 contributes to progressive nephropathy. Scientific reports 25 32047249
2014 TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions. Cellular and molecular life sciences : CMLS 25 24858416
2021 Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy. Cancer letters 24 34752845
2021 TRPM7 Ion Channel: Oncogenic Roles and Therapeutic Potential in Breast Cancer. Cancers 24 34944940
2020 TRPM7 activation potentiates SOCE in enamel cells but requires ORAI. Cell calcium 24 32146159
2019 Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function. Molecular neurobiology 24 31392516
2018 TRPM7 in CHBP-induced renoprotection upon ischemia reperfusion-related injury. Scientific reports 24 29615639
2018 The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells. Science signaling 24 29871912
2022 TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt. Communications biology 23 35882956
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 23 36095216
2020 Suppression of TRPM7 enhances TRAIL-induced apoptosis in triple-negative breast cancer cells. Journal of cellular physiology 23 32468675
2020 Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions. Cell calcium 23 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
2023 Adipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice. Nature communications 21 36717580
2022 Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7. Cell calcium 21 36027648
2021 Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases. Immunology 21 34558663
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 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 20 36972446
2021 Tumor suppressor miR-192-5p targets TRPM7 and inhibits proliferation and invasion in cervical cancer. The Kaohsiung journal of medical sciences 20 34042256
2020 Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead. Acta pharmacologica Sinica 20 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
2024 The Role of TRPM7 in Oncogenesis. International journal of molecular sciences 18 38255793
2024 Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7. Nature communications 18 39353909
2020 A bibliometric analysis and review of recent researches on TRPM7. Channels (Austin, Tex.) 18 32643506
2012 Differential expression of TRPM7 in rat hepatoma and embryonic and adult hepatocytes. Canadian journal of physiology and pharmacology 18 22429021

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