{"gene":"TRPM7","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"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.","method":"Electrophysiology (whole-cell patch-clamp in HEK-293 overexpression and native cells), targeted gene deletion in DT-40 B cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional channel characterization by electrophysiology combined with genetic knockout showing lethality, replicated across cell types","pmids":["11385574"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Electrophysiology (CHO-K1 expression), site-directed mutagenesis of kinase active site, autophosphorylation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with mutagenesis in single rigorous paper; foundational characterization replicated by subsequent work","pmids":["11161216"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation (kinase–PLC C2 domain interaction), electrophysiology in native cardiac cells and heterologous systems, receptor stimulation and PIP2 manipulation experiments","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay combined with functional electrophysiology across multiple experimental systems, multiple orthogonal methods","pmids":["11941371"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro kinase assay with bacterially expressed kinase domain, substrate phosphorylation, cofactor titrations","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro kinase with multiple substrates and pharmacological characterization in single rigorous paper","pmids":["14594813"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Whole-cell patch-clamp, receptor agonist/antagonist pharmacology, kinase-dead TRPM7 mutants, PKA inhibitors (H89, KT5720)","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — electrophysiology with kinase-dead mutants and PKA inhibitors, multiple orthogonal approaches in one study","pmids":["15069188"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Site-directed mutagenesis of autophosphorylation and catalytic sites, mass spectrometry identification of phosphorylation sites, whole-cell patch-clamp, Ca2+ influx assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with MS phosphosite identification and functional electrophysiology in one rigorous study","pmids":["15781465"],"is_preprint":false},{"year":2006,"finding":"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.","method":"In vitro kinase assay (myosin IIA heavy chain phosphorylation), live-cell imaging, co-immunoprecipitation, overexpression/pharmacological inhibition of myosin II","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct substrate phosphorylation combined with cellular functional assays and pharmacology in one focused study","pmids":["16407977"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Whole-cell patch-clamp of heterologously expressed and endogenous TRPM7, pharmacological manipulation of halide concentrations and kinase ATP-binding site","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological dissection, single lab, multiple conditions","pmids":["23471296"],"is_preprint":false},{"year":2011,"finding":"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.","method":"RNA interference, pulldown/GTPase activation assay (Rac/Cdc42), wound-healing assay, SLC41A2 rescue expression","journal":"Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with GTPase pulldown and rescue experiments, single lab","pmids":["21208190"],"is_preprint":false},{"year":2013,"finding":"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.","method":"RNA interference (siRNA knockdown), migration/invasion assays, western blotting for pathway phosphorylation","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, siRNA knockdown with pathway readout, no mutagenesis or rescue","pmids":["23353055"],"is_preprint":false},{"year":2013,"finding":"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.","method":"TIRF Ca2+ fluorometry, TRPM7 channel inhibitor (waixenicin-A), knockdown, live-cell imaging","journal":"Cell Calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with pharmacological and genetic inhibition, two orthogonal methods","pmids":["24176224"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Conditional B cell-specific TRPM7 knockout mice, kinase-dead knock-in mice, in vitro rescue with Mg2+ supplementation, flow cytometry","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models (conditional KO and kinase-dead knock-in) with in vitro rescue, multiple orthogonal approaches","pmids":["29871911"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Mast cell degranulation assays, histamine release measurement, TRPM7 kinase-dead knock-in mice (TRPM7KR) vs kinase-deletion mice (TRPM7+/ΔK), GPCR stimulation experiments","journal":"Journal of Physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse models (kinase-dead point mutation vs kinase-deletion), functional degranulation assays, dissection of channel vs kinase contributions","pmids":["26660477"],"is_preprint":false},{"year":2017,"finding":"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.","method":"TRPM7 kinase-dead mutant mice (Trpm7 R/R), T cell gut colonization assays, SMAD2 phosphorylation analysis, Th17/Treg differentiation experiments","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic kinase-dead mouse model with mechanistic downstream (SMAD2) analysis and functional T cell assays","pmids":["29203869"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Trpm7 kinase-dead knock-in mice, platelet Ca2+ mobilization assays, phosphoprotein western blotting, in vivo arterial thrombosis and stroke models","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic kinase-dead mouse model with mechanistic phosphorylation readouts and in vivo disease models","pmids":["29146750"],"is_preprint":false},{"year":2017,"finding":"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.","method":"TRPM7−/− DT40 B cells, kinase-deficient mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ flux measurements, CRAC current recordings","journal":"Journal of Physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout combined with kinase-dead mutants and pharmacological inhibition, multiple orthogonal approaches","pmids":["28130783"],"is_preprint":false},{"year":2018,"finding":"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.","method":"TRPM7-deficient DT40 B cells, kinase-deficient mutant, antigen gathering/internalization assays, BCR signaling analysis, lipid metabolism profiling","journal":"Science Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic models with functional B cell assays, PLCγ2 as kinase substrate proposed but not directly demonstrated by in vitro phosphorylation","pmids":["29871912"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Pharmacological TRPM7 inhibition (NS8593), genome editing, RhoA activity assay, actin polymerization assay, MRTF-A localization imaging, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular and in vivo methods, but RhoA phosphorylation by TRPM7 kinase not directly confirmed by in vitro kinase assay","pmids":["31844251"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Multi-epitope affinity purification, high-resolution quantitative mass spectrometry, heterologous reconstitution co-immunoprecipitation, functional TRPM7 activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS-based native complex identification from brain tissue combined with functional reconstitution in heterologous system, multiple orthogonal methods","pmids":["34766907"],"is_preprint":false},{"year":2021,"finding":"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.","method":"TRPM7 kinase fragment nuclear localization (fractionation/imaging), chromatin immunoprecipitation (H3S10 phosphorylation at cytokine promoters), TRPM7-dependent Mg2+ influx assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear fractionation and ChIP combined with TRPM7-specific knockdown, single lab","pmids":["34001887"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Pharmacological TRPM7 channel and kinase inhibition (TG100-115), murine neutrophils with genetic kinase ablation, transmigration assay, ROS measurement, Akt1/mTOR phosphorylation western blotting","journal":"Frontiers in Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic kinase ablation confirmed by pharmacological inhibitor, functional neutrophil assays with pathway readout","pmids":["33658993"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA screen, perforated-patch electrophysiology, phagosomal pH measurements, genetically-encoded Ca2+ sensors in mice","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiology of endosomal current combined with in vivo Ca2+ imaging and functional phagosome maturation assays, multiple orthogonal methods","pmids":["35680919"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Palmitoylation assay, RUSH trafficking system (live imaging), zDHHC enzyme identification (co-expression/knockdown), Ca2+ flux measurement with non-palmitoylatable mutants","journal":"Cell Calcium","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct palmitoylation assay combined with live trafficking imaging and functional Ca2+ measurement with mutants, multiple orthogonal methods in single study","pmids":["36027648"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Site-directed mutagenesis, whole-cell and single-channel patch-clamp, molecular dynamics simulations","journal":"Cellular and Molecular Life Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional electrophysiology validated by MD simulations, structure-function relationship established","pmids":["35389104"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cryo-EM structure determination, functional electrophysiology, molecular dynamics simulations, inhibitor binding site mapping","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with functional validation and MD simulations in one rigorous study","pmids":["37156763"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA-seq, metabolomics, TRPM7 genetic deletion, rescue with constitutively active CRTC2/CREB, Ca2+ imaging, xenograft models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with transcriptional rescue experiments and pathway dissection, single lab","pmids":["36878949"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genetically encoded Mg2+ reporter, co-immunoprecipitation (CNNM3/TRPM7/ARL15 complex), PRL-2 overexpression/knockdown, functional Mg2+ transport assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein complex co-IP with functional readout using Mg2+ reporter, single lab, multiple interactors tested","pmids":["36972446"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Kinase cross-phosphorylation assays, intracellular trafficking experiments, DT40 TRPM7-deficient complementation, surface labeling, TRPM6 kinase-dead mutant co-expression","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase assay plus functional cellular growth and trafficking experiments, single lab","pmids":["24858416"],"is_preprint":false},{"year":2022,"finding":"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.","method":"TRPM7 knockdown and pharmacological inhibition, PKCα-NOX4 co-immunoprecipitation, Ca2+ imaging, AAV9-mediated TRPM7 silencing in vivo, ferroptosis assays","journal":"Redox Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for PKCα/NOX4 complex with genetic and pharmacological TRPM7 inhibition, functional ferroptosis readout, single lab","pmids":["35917680"],"is_preprint":false},{"year":2024,"finding":"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.","method":"TRPM7 knockout/knockdown, multiple viral infection systems (pseudovirus and authentic virus), endosomal pH measurements, electrophysiology of TRPM7 currents","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function across multiple viral systems with mechanistic endosomal pH and electrophysiology measurements, multiple orthogonal approaches","pmids":["39353909"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence co-localization, TRPM7 shRNA knockdown, pharmacological channel block (waixenicin A), Ca2+ imaging, neurite outgrowth assay","journal":"Molecular Neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and co-localization with functional knockdown and pharmacological evidence, single lab","pmids":["25502295"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Patch-clamp analysis, Ca2+ and Na+ imaging, site-directed mutagenesis (A931T, F971A, W972A), transfection of trigeminal ganglion neurons","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with electrophysiology in expression system and native neurons, single lab","pmids":["36095216"],"is_preprint":false},{"year":2021,"finding":"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.","method":"TRPM7 agonist treatment (clozapine, naltriben), Zn2+ imaging, autophagosome-lysosome fusion assay, co-immunoprecipitation (Sxt17/VAMP8), in vivo xenograft models","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with co-IP and Zn2+ imaging combined with in vivo validation, single lab","pmids":["34752845"],"is_preprint":false},{"year":2020,"finding":"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.","method":"TRPM7 kinase-deletion mice, cardiac histology, macrophage-fibroblast co-culture, calpain activity assay, intravital microscopy","journal":"Cardiovascular Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with co-culture mechanistic experiments, single lab","pmids":["31250885"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Whole-cell patch-clamp, CaMKII inhibitor pharmacology (W-7, staurosporine, KN-93, CaMKII inhibitory peptide), Mg2+/Mg-ATP dialysis","journal":"American Journal of Physiology – Gastrointestinal and Liver Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological dissection of Ca2+/CaMKII pathway, single lab","pmids":["19661151"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Pharmacological TRPM7 inhibition (NS8593), targeted genome editing, RhoA activity assay, MRTF-A nuclear localization imaging, actin polymerization assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches with signaling pathway readouts, single lab; RhoA direct phosphorylation by TRPM7 kinase inferred but not shown by direct in vitro assay","pmids":["31844251"],"is_preprint":false}],"current_model":"TRPM7 is a ubiquitously expressed bifunctional 'chanzyme' comprising a divalent cation-permeable ion channel (conducting Ca2+, Mg2+, Zn2+ and other metals) and a C-terminal alpha-kinase domain; the channel is constitutively active but strongly inhibited by intracellular free Mg2+ binding to a conserved N1097 gate, by Mg·ATP/GTP, by PIP2 depletion downstream of PLC-coupled receptors, and by chloride/halides through the kinase ATP-binding site, while being potentiated by cAMP/PKA in a manner requiring an intact kinase domain; the kinase phosphorylates substrates including myosin IIA heavy chain, histone H3 (Ser10), annexin A1, and SMAD2, and is regulated by TRPM6 cross-phosphorylation; channel-mediated Mg2+ and Zn2+ fluxes control downstream effectors including calcineurin/CRTC2/CREB-driven glycolytic reprogramming, CaMKII-dependent Ca2+ inhibition, RhoA/actomyosin contractility, and endosomal acidification; the cleaved kinase fragment translocates to the nucleus to remodel chromatin; TRPM7 activity is further controlled by palmitoylation (by zDHHC17/zDHHC5) that governs trafficking between the cell surface and intracellular vesicles, and by its assembly into native TRPM7/CNNM/ARL15 ternary complexes that modulate its activity; collectively, TRPM7 integrates the metabolic/ionic state of the cell to regulate Mg2+ and Ca2+ homeostasis, cytoskeletal dynamics, immune cell function, phagosome maturation, cell survival, and gene expression."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2001,"claim":"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","pmids":["11385574","11161216"],"confidence":"High","gaps":["Did not resolve whether kinase catalysis vs domain structure underlies the channel requirement","No structural basis for ion selectivity"]},{"year":2002,"claim":"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","pmids":["11941371"],"confidence":"High","gaps":["Stoichiometry of PIP2 binding to the channel not defined","Did not separate PIP2 depletion from concurrent Ca2+ changes"]},{"year":2003,"claim":"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","pmids":["14594813"],"confidence":"High","gaps":["Physiological substrates not identified at this stage","No structure of the active site"]},{"year":2004,"claim":"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","pmids":["15069188"],"confidence":"High","gaps":["PKA phosphorylation site on TRPM7 not mapped","Mechanism of kinase-domain requirement unresolved"]},{"year":2005,"claim":"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","pmids":["15781465"],"confidence":"High","gaps":["How the kinase domain supports assembly/localization not mechanistically defined","Function of autophosphorylation sites unknown"]},{"year":2006,"claim":"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","pmids":["16407977"],"confidence":"High","gaps":["Did not quantify in vivo phosphostoichiometry","Channel vs kinase contributions to each phenotype not fully separated"]},{"year":2009,"claim":"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","pmids":["19661151"],"confidence":"Medium","gaps":["CaMKII phosphorylation site on TRPM7 not mapped","Single lab, native-current identity inferred"]},{"year":2011,"claim":"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","pmids":["21208190"],"confidence":"Medium","gaps":["Direct link between Mg2+ and GTPase activation not biochemically defined","Single lab"]},{"year":2013,"claim":"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","pmids":["23471296","23353055","24176224"],"confidence":"Medium","gaps":["No mutagenesis/rescue for the MAPK link","Mechanism coupling halide binding to gating not structurally resolved"]},{"year":2014,"claim":"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","pmids":["29871911","24858416","25502295"],"confidence":"High","gaps":["Direction and sites of TRPM6→TRPM7 phosphorylation not fully mapped in vivo","Growth-cone work single lab"]},{"year":2016,"claim":"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","pmids":["26660477"],"confidence":"High","gaps":["Kinase substrate in the exocytic machinery not identified","Link to Ca2+ sensitivity mechanism unresolved"]},{"year":2017,"claim":"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","pmids":["29203869","29146750","28130783"],"confidence":"High","gaps":["Direct kinase phosphorylation of SMAD2/PLC substrates not shown in vitro","How kinase modulates SOCE mechanistically unresolved"]},{"year":2018,"claim":"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","pmids":["29871912"],"confidence":"Medium","gaps":["PLCγ2 not validated as direct substrate by in vitro phosphorylation","Single lab"]},{"year":2019,"claim":"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","pmids":["31844251","31250885"],"confidence":"Medium","gaps":["RhoA phosphorylation by TRPM7 kinase not confirmed by direct in vitro assay","Cardiac kinase-deletion phenotype mechanism (calpain) correlative"]},{"year":2021,"claim":"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","pmids":["34766907","34001887","34752845","33658993"],"confidence":"High","gaps":["Protease generating the nuclear fragment not identified","Functional consequence of CNNM/ARL15 binding on gating not structurally resolved"]},{"year":2022,"claim":"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","pmids":["35389104","36027648","35680919","35917680","36095216"],"confidence":"High","gaps":["Coupling between palmitoylation and gating not mechanistically resolved","A931T variant not linked to a defined human disease in the corpus"]},{"year":2023,"claim":"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","pmids":["36878949","36972446","37156763"],"confidence":"Medium","gaps":["Direct transcriptional target validation limited to single lab","Inhibitor binding site not yet exploited therapeutically in the corpus"]},{"year":2024,"claim":"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","pmids":["39353909"],"confidence":"High","gaps":["Endosomal vs plasma-membrane channel pool not distinguished","Therapeutic exploitation not tested in vivo"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,11,21,29]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,6,13,14]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,22,29]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[22,32]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[21,29]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,30]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,25]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12,13,14,20,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[17,19,25]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[29]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,18,26]}],"complexes":["TRPM7/CNNM/ARL15 ternary complex"],"partners":["PLCB (PLC)","CNNM3","ARL15","TRPM6","MYH9 (MYOSIN IIA)","ACTN1 (Α-ACTININ-1)","ZDHHC17","ZDHHC5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QT4","full_name":"Transient receptor potential cation channel subfamily M member 7","aliases":["Channel-kinase 1","Long transient receptor potential channel 7","LTrpC-7","LTrpC7"],"length_aa":1865,"mass_kda":212.7,"function":"Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. The channel is highly permeable to divalent cations, specifically calcium (Ca2+), magnesium (Mg2+) and zinc (Zn2+) and mediates their influx (PubMed:11385574, PubMed:12887921, PubMed:15485879, PubMed:24316671, PubMed:35561741, PubMed:36027648). Controls a wide range of biological processes such as Ca2(+), Mg(2+) and Zn(2+) homeostasis, vesicular Zn(2+) release channel and intracellular Ca(2+) signaling, embryonic development, immune responses, cell motility, proliferation and differentiation (By similarity). The C-terminal alpha-kinase domain autophosphorylates cytoplasmic residues of TRPM7 (PubMed:18365021). In vivo, TRPM7 phosphorylates SMAD2, suggesting that TRPM7 kinase may play a role in activating SMAD signaling pathways. In vitro, TRPM7 kinase phosphorylates ANXA1 (annexin A1), myosin II isoforms and a variety of proteins with diverse cellular functions (PubMed:15485879, PubMed:18394644) The cleaved channel exhibits substantially higher current and potentiates Fas receptor signaling The C-terminal kinase domain can be cleaved from the channel segment in a cell-type-specific fashion. In immune cells, the TRPM7 kinase domain is clipped from the channel domain by caspases in response to Fas-receptor stimulation. The cleaved kinase fragments can translocate to the nucleus, and bind chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to ultimately phosphorylate specific Ser/Thr residues of histones known to be functionally important for cell differentiation and embryonic development","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96QT4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPM7","classification":"Common Essential","n_dependent_lines":764,"n_total_lines":1208,"dependency_fraction":0.6324503311258278},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000092439","cell_line_id":"CID001664","localizations":[{"compartment":"membrane","grade":3},{"compartment":"er","grade":1}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001664","total_profiled":1310},"omim":[{"mim_id":"607803","title":"CYCLIN M2; CNNM2","url":"https://www.omim.org/entry/607803"},{"mim_id":"607009","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 6; TRPM6","url":"https://www.omim.org/entry/607009"},{"mim_id":"605692","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 7; TRPM7","url":"https://www.omim.org/entry/605692"},{"mim_id":"602014","title":"HYPOMAGNESEMIA 1, INTESTINAL; HOMG1","url":"https://www.omim.org/entry/602014"},{"mim_id":"600144","title":"INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 2; ITPR2","url":"https://www.omim.org/entry/600144"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":102.5}],"url":"https://www.proteinatlas.org/search/TRPM7"},"hgnc":{"alias_symbol":["CHAK1","LTRPC7","TRP-PLIK"],"prev_symbol":[]},"alphafold":{"accession":"Q96QT4","domains":[{"cath_id":"-","chopping":"93-131_143-150_173-291","consensus_level":"medium","plddt":85.6779,"start":93,"end":291},{"cath_id":"-","chopping":"1009-1062_1085-1149","consensus_level":"medium","plddt":82.3171,"start":1009,"end":1149},{"cath_id":"3.30.200.20","chopping":"1581-1820","consensus_level":"medium","plddt":82.9054,"start":1581,"end":1820}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QT4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QT4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QT4-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPM7","jax_strain_url":"https://www.jax.org/strain/search?query=TRPM7"},"sequence":{"accession":"Q96QT4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QT4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QT4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QT4"}},"corpus_meta":[{"pmid":"11385574","id":"PMC_11385574","title":"LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11385574","citation_count":810,"is_preprint":false},{"pmid":"11161216","id":"PMC_11161216","title":"TRP-PLIK, a bifunctional protein with kinase and ion channel activities.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11161216","citation_count":616,"is_preprint":false},{"pmid":"11941371","id":"PMC_11941371","title":"The TRPM7 channel is inactivated by PIP(2) hydrolysis.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11941371","citation_count":428,"is_preprint":false},{"pmid":"16407977","id":"PMC_16407977","title":"TRPM7, a novel regulator of actomyosin contractility and cell adhesion.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16407977","citation_count":299,"is_preprint":false},{"pmid":"34001887","id":"PMC_34001887","title":"TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34001887","citation_count":245,"is_preprint":false},{"pmid":"17481860","id":"PMC_17481860","title":"TRPM6 and TRPM7--Gatekeepers of human magnesium metabolism.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17481860","citation_count":211,"is_preprint":false},{"pmid":"14594813","id":"PMC_14594813","title":"Characterization of the protein kinase activity of TRPM7/ChaK1, a protein kinase fused to the transient receptor potential ion channel.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14594813","citation_count":164,"is_preprint":false},{"pmid":"15781465","id":"PMC_15781465","title":"Channel function is dissociated from the intrinsic kinase activity and autophosphorylation of TRPM7/ChaK1.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15781465","citation_count":161,"is_preprint":false},{"pmid":"15069188","id":"PMC_15069188","title":"Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15069188","citation_count":147,"is_preprint":false},{"pmid":"30995736","id":"PMC_30995736","title":"TRPM7, Magnesium, and Signaling.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30995736","citation_count":131,"is_preprint":false},{"pmid":"23353055","id":"PMC_23353055","title":"TRPM7 mediates breast cancer cell migration and invasion through the MAPK pathway.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23353055","citation_count":128,"is_preprint":false},{"pmid":"25965832","id":"PMC_25965832","title":"Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25965832","citation_count":117,"is_preprint":false},{"pmid":"25192910","id":"PMC_25192910","title":"TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25192910","citation_count":100,"is_preprint":false},{"pmid":"28130783","id":"PMC_28130783","title":"The TRPM7 channel kinase regulates store-operated calcium entry.","date":"2017","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28130783","citation_count":96,"is_preprint":false},{"pmid":"24756720","id":"PMC_24756720","title":"TRPM7.","date":"2014","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24756720","citation_count":95,"is_preprint":false},{"pmid":"31250885","id":"PMC_31250885","title":"Chanzyme TRPM7 protects against cardiovascular inflammation and fibrosis.","date":"2020","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/31250885","citation_count":93,"is_preprint":false},{"pmid":"35917680","id":"PMC_35917680","title":"TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35917680","citation_count":88,"is_preprint":false},{"pmid":"29203869","id":"PMC_29203869","title":"TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29203869","citation_count":87,"is_preprint":false},{"pmid":"25205764","id":"PMC_25205764","title":"TRPM7 regulates proliferation and polarisation of macrophages.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25205764","citation_count":83,"is_preprint":false},{"pmid":"17217066","id":"PMC_17217066","title":"The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7.","date":"2007","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17217066","citation_count":78,"is_preprint":false},{"pmid":"28379203","id":"PMC_28379203","title":"Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target.","date":"2017","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/28379203","citation_count":76,"is_preprint":false},{"pmid":"36332746","id":"PMC_36332746","title":"A pan-cancer-bioinformatic-based literature review of TRPM7 in cancers.","date":"2022","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36332746","citation_count":74,"is_preprint":false},{"pmid":"35101076","id":"PMC_35101076","title":"TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35101076","citation_count":73,"is_preprint":false},{"pmid":"24769209","id":"PMC_24769209","title":"Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24769209","citation_count":72,"is_preprint":false},{"pmid":"21290295","id":"PMC_21290295","title":"TRPM7, the Mg(2+) inhibited channel and kinase.","date":"2011","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21290295","citation_count":71,"is_preprint":false},{"pmid":"25073440","id":"PMC_25073440","title":"Function and regulation of the channel-kinase TRPM7 in health and disease.","date":"2014","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25073440","citation_count":70,"is_preprint":false},{"pmid":"17395433","id":"PMC_17395433","title":"TRPM7 and TRPM2-Candidate susceptibility genes for Western Pacific ALS and PD?","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17395433","citation_count":70,"is_preprint":false},{"pmid":"21208190","id":"PMC_21208190","title":"TRPM7 regulates polarized cell movements.","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21208190","citation_count":70,"is_preprint":false},{"pmid":"22634382","id":"PMC_22634382","title":"TRPM7: a unique channel involved in magnesium homeostasis.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22634382","citation_count":70,"is_preprint":false},{"pmid":"26218331","id":"PMC_26218331","title":"TRPM7 and its role in neurodegenerative diseases.","date":"2015","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26218331","citation_count":69,"is_preprint":false},{"pmid":"20567598","id":"PMC_20567598","title":"Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20567598","citation_count":65,"is_preprint":false},{"pmid":"20932259","id":"PMC_20932259","title":"TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions.","date":"2011","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20932259","citation_count":64,"is_preprint":false},{"pmid":"21150127","id":"PMC_21150127","title":"Transient receptor potential melastatin 7 (TRPM7) cation channels, magnesium and the vascular system in hypertension.","date":"2010","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/21150127","citation_count":61,"is_preprint":false},{"pmid":"27662662","id":"PMC_27662662","title":"Decreased TRPM7 inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27662662","citation_count":61,"is_preprint":false},{"pmid":"24176224","id":"PMC_24176224","title":"TRPM7 triggers Ca2+ sparks and invadosome formation in neuroblastoma cells.","date":"2013","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/24176224","citation_count":60,"is_preprint":false},{"pmid":"37156763","id":"PMC_37156763","title":"Structural mechanisms of TRPM7 activation and inhibition.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37156763","citation_count":59,"is_preprint":false},{"pmid":"15746380","id":"PMC_15746380","title":"TRPM7 and ischemic CNS injury.","date":"2005","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/15746380","citation_count":58,"is_preprint":false},{"pmid":"29146750","id":"PMC_29146750","title":"TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice.","date":"2017","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29146750","citation_count":58,"is_preprint":false},{"pmid":"25502295","id":"PMC_25502295","title":"TRPM7 Regulates Axonal Outgrowth and Maturation of Primary Hippocampal Neurons.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25502295","citation_count":58,"is_preprint":false},{"pmid":"30126133","id":"PMC_30126133","title":"The Channel-Kinase TRPM7 as Novel Regulator of Immune System Homeostasis.","date":"2018","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30126133","citation_count":53,"is_preprint":false},{"pmid":"25437439","id":"PMC_25437439","title":"Natural and Synthetic Modulators of the TRPM7 Channel.","date":"2014","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/25437439","citation_count":53,"is_preprint":false},{"pmid":"25450691","id":"PMC_25450691","title":"TRPM7 is required for ovarian cancer cell growth, migration and invasion.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25450691","citation_count":49,"is_preprint":false},{"pmid":"28061441","id":"PMC_28061441","title":"Activation of TRPM7 by naltriben enhances migration and invasion of glioblastoma cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28061441","citation_count":45,"is_preprint":false},{"pmid":"21552293","id":"PMC_21552293","title":"TRPM7 in cerebral ischemia and potential target for drug development in stroke.","date":"2011","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21552293","citation_count":44,"is_preprint":false},{"pmid":"34766907","id":"PMC_34766907","title":"The molecular appearance of native TRPM7 channel complexes identified by high-resolution proteomics.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34766907","citation_count":43,"is_preprint":false},{"pmid":"24278689","id":"PMC_24278689","title":"TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets.","date":"2012","source":"Scientifica","url":"https://pubmed.ncbi.nlm.nih.gov/24278689","citation_count":42,"is_preprint":false},{"pmid":"24634592","id":"PMC_24634592","title":"The Pathophysiologic Roles of TRPM7 Channel.","date":"2014","source":"The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24634592","citation_count":41,"is_preprint":false},{"pmid":"25472964","id":"PMC_25472964","title":"TRPM7 regulates vascular endothelial cell adhesion and tube formation.","date":"2014","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25472964","citation_count":41,"is_preprint":false},{"pmid":"31844251","id":"PMC_31844251","title":"Inhibition of TRPM7 blocks MRTF/SRF-dependent transcriptional and tumorigenic activity.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31844251","citation_count":41,"is_preprint":false},{"pmid":"28533887","id":"PMC_28533887","title":"Lidocaine suppresses glioma cell proliferation by inhibiting TRPM7 channels.","date":"2017","source":"International journal of physiology, pathophysiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28533887","citation_count":41,"is_preprint":false},{"pmid":"16001276","id":"PMC_16001276","title":"TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors.","date":"2005","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16001276","citation_count":40,"is_preprint":false},{"pmid":"28356194","id":"PMC_28356194","title":"Assessment of TRPM7 functions by drug-like small molecules.","date":"2017","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/28356194","citation_count":40,"is_preprint":false},{"pmid":"26660477","id":"PMC_26660477","title":"TRPM7 kinase activity regulates murine mast cell degranulation.","date":"2016","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26660477","citation_count":40,"is_preprint":false},{"pmid":"29489440","id":"PMC_29489440","title":"TRPM7 Mediates Mechanosensitivity in Adult Rat Odontoblasts.","date":"2018","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/29489440","citation_count":39,"is_preprint":false},{"pmid":"36878949","id":"PMC_36878949","title":"The TRPM7 channel reprograms cellular glycolysis to drive tumorigenesis and angiogenesis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36878949","citation_count":37,"is_preprint":false},{"pmid":"19661151","id":"PMC_19661151","title":"Mg2+- and MgATP-inhibited and Ca2+/calmodulin-sensitive TRPM7-like current in hepatoma and hepatocytes.","date":"2009","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19661151","citation_count":36,"is_preprint":false},{"pmid":"35680919","id":"PMC_35680919","title":"Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35680919","citation_count":34,"is_preprint":false},{"pmid":"33784560","id":"PMC_33784560","title":"Role of TRPM7 kinase in cancer.","date":"2021","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/33784560","citation_count":33,"is_preprint":false},{"pmid":"32733880","id":"PMC_32733880","title":"TRPM7/RPSA Complex Regulates Pancreatic Cancer Cell Migration.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32733880","citation_count":33,"is_preprint":false},{"pmid":"23471296","id":"PMC_23471296","title":"TRPM7 is regulated by halides through its kinase domain.","date":"2013","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/23471296","citation_count":32,"is_preprint":false},{"pmid":"25169754","id":"PMC_25169754","title":"Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity.","date":"2014","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25169754","citation_count":31,"is_preprint":false},{"pmid":"33153718","id":"PMC_33153718","title":"TRPM7 modulates macrophage polarization by STAT1/STAT6 pathways in RAW264.7 cells.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33153718","citation_count":30,"is_preprint":false},{"pmid":"27891609","id":"PMC_27891609","title":"Role of TRPM7 in cerebral ischaemia and hypoxia.","date":"2017","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27891609","citation_count":29,"is_preprint":false},{"pmid":"33658993","id":"PMC_33658993","title":"TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33658993","citation_count":29,"is_preprint":false},{"pmid":"31073743","id":"PMC_31073743","title":"Role of the chanzyme TRPM7 in the nervous system in health and disease.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31073743","citation_count":29,"is_preprint":false},{"pmid":"34175300","id":"PMC_34175300","title":"Cell death modulation by transient receptor potential melastatin channels TRPM2 and TRPM7 and their underlying molecular mechanisms.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34175300","citation_count":28,"is_preprint":false},{"pmid":"32505565","id":"PMC_32505565","title":"TRPM7 is overexpressed in human IBD-related and sporadic colorectal cancer and correlates with tumor grade.","date":"2020","source":"Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/32505565","citation_count":28,"is_preprint":false},{"pmid":"33381038","id":"PMC_33381038","title":"TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33381038","citation_count":27,"is_preprint":false},{"pmid":"32977698","id":"PMC_32977698","title":"Mapping TRPM7 Function by NS8593.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32977698","citation_count":26,"is_preprint":false},{"pmid":"35389104","id":"PMC_35389104","title":"Structural mechanism of TRPM7 channel regulation by intracellular magnesium.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35389104","citation_count":26,"is_preprint":false},{"pmid":"32047249","id":"PMC_32047249","title":"TRPM7 contributes to progressive nephropathy.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32047249","citation_count":25,"is_preprint":false},{"pmid":"24858416","id":"PMC_24858416","title":"TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions.","date":"2014","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/24858416","citation_count":25,"is_preprint":false},{"pmid":"34752845","id":"PMC_34752845","title":"Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34752845","citation_count":24,"is_preprint":false},{"pmid":"31392516","id":"PMC_31392516","title":"Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function.","date":"2019","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31392516","citation_count":24,"is_preprint":false},{"pmid":"34944940","id":"PMC_34944940","title":"TRPM7 Ion Channel: Oncogenic Roles and Therapeutic Potential in Breast Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34944940","citation_count":24,"is_preprint":false},{"pmid":"29871912","id":"PMC_29871912","title":"The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29871912","citation_count":24,"is_preprint":false},{"pmid":"29615639","id":"PMC_29615639","title":"TRPM7 in CHBP-induced renoprotection upon ischemia reperfusion-related injury.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29615639","citation_count":24,"is_preprint":false},{"pmid":"32146159","id":"PMC_32146159","title":"TRPM7 activation potentiates SOCE in enamel cells but requires ORAI.","date":"2020","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/32146159","citation_count":24,"is_preprint":false},{"pmid":"35882956","id":"PMC_35882956","title":"TRPM7 deficiency exacerbates cardiovascular and renal damage induced by aldosterone-salt.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35882956","citation_count":23,"is_preprint":false},{"pmid":"33080445","id":"PMC_33080445","title":"Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions.","date":"2020","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/33080445","citation_count":23,"is_preprint":false},{"pmid":"36095216","id":"PMC_36095216","title":"A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36095216","citation_count":23,"is_preprint":false},{"pmid":"32468675","id":"PMC_32468675","title":"Suppression of TRPM7 enhances TRAIL-induced apoptosis in triple-negative breast cancer cells.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32468675","citation_count":23,"is_preprint":false},{"pmid":"31640089","id":"PMC_31640089","title":"TRPM7 deficiency suppresses cell proliferation, migration, and invasion in human colorectal cancer via regulation of epithelial-mesenchymal transition.","date":"2019","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/31640089","citation_count":22,"is_preprint":false},{"pmid":"34558663","id":"PMC_34558663","title":"Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases.","date":"2021","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34558663","citation_count":21,"is_preprint":false},{"pmid":"26179995","id":"PMC_26179995","title":"The Different Roles of The Channel-Kinases TRPM6 and TRPM7.","date":"2015","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26179995","citation_count":21,"is_preprint":false},{"pmid":"25204892","id":"PMC_25204892","title":"Novel insights into TRPM7 function in fibrotic diseases: a potential therapeutic target.","date":"2015","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25204892","citation_count":21,"is_preprint":false},{"pmid":"31219801","id":"PMC_31219801","title":"TRPM7 channel inhibition exacerbates pulmonary arterial hypertension through MEK/ERK pathway.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31219801","citation_count":21,"is_preprint":false},{"pmid":"31444399","id":"PMC_31444399","title":"TRPM7 mediates kidney injury, endothelial hyperpermeability and mortality during endotoxemia.","date":"2019","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31444399","citation_count":21,"is_preprint":false},{"pmid":"36027648","id":"PMC_36027648","title":"Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7.","date":"2022","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/36027648","citation_count":21,"is_preprint":false},{"pmid":"29871911","id":"PMC_29871911","title":"The ion channel TRPM7 is required for B cell lymphopoiesis.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29871911","citation_count":21,"is_preprint":false},{"pmid":"36717580","id":"PMC_36717580","title":"Adipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36717580","citation_count":21,"is_preprint":false},{"pmid":"36972446","id":"PMC_36972446","title":"PRL-1/2 phosphatases control TRPM7 magnesium-dependent function to regulate cellular bioenergetics.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36972446","citation_count":20,"is_preprint":false},{"pmid":"32994545","id":"PMC_32994545","title":"Waixenicin A, a marine-derived TRPM7 inhibitor: a promising CNS drug lead.","date":"2020","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/32994545","citation_count":20,"is_preprint":false},{"pmid":"34042256","id":"PMC_34042256","title":"Tumor suppressor miR-192-5p targets TRPM7 and inhibits proliferation and invasion in cervical cancer.","date":"2021","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34042256","citation_count":20,"is_preprint":false},{"pmid":"31060485","id":"PMC_31060485","title":"Roles of TRPM7 in Renal Ischemia-Reperfusion Injury.","date":"2019","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/31060485","citation_count":19,"is_preprint":false},{"pmid":"23247582","id":"PMC_23247582","title":"TRPM7, the cytoskeleton and neuronal death.","date":"2012","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23247582","citation_count":19,"is_preprint":false},{"pmid":"38255793","id":"PMC_38255793","title":"The Role of TRPM7 in Oncogenesis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38255793","citation_count":18,"is_preprint":false},{"pmid":"39353909","id":"PMC_39353909","title":"Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39353909","citation_count":18,"is_preprint":false},{"pmid":"32643506","id":"PMC_32643506","title":"A bibliometric analysis and review of recent researches on TRPM7.","date":"2020","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32643506","citation_count":18,"is_preprint":false},{"pmid":"22429021","id":"PMC_22429021","title":"Differential expression of TRPM7 in rat hepatoma and embryonic and adult hepatocytes.","date":"2012","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22429021","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47185,"output_tokens":9081,"usd":0.138885,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19173,"output_tokens":6560,"usd":0.129933,"stage2_stop_reason":"end_turn"},"total_usd":0.268818,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology (whole-cell patch-clamp in HEK-293 overexpression and native cells), targeted gene deletion in DT-40 B cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional channel characterization by electrophysiology combined with genetic knockout showing lethality, replicated across cell types\",\n      \"pmids\": [\"11385574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology (CHO-K1 expression), site-directed mutagenesis of kinase active site, autophosphorylation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with mutagenesis in single rigorous paper; foundational characterization replicated by subsequent work\",\n      \"pmids\": [\"11161216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (kinase–PLC C2 domain interaction), electrophysiology in native cardiac cells and heterologous systems, receptor stimulation and PIP2 manipulation experiments\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay combined with functional electrophysiology across multiple experimental systems, multiple orthogonal methods\",\n      \"pmids\": [\"11941371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay with bacterially expressed kinase domain, substrate phosphorylation, cofactor titrations\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro kinase with multiple substrates and pharmacological characterization in single rigorous paper\",\n      \"pmids\": [\"14594813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp, receptor agonist/antagonist pharmacology, kinase-dead TRPM7 mutants, PKA inhibitors (H89, KT5720)\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — electrophysiology with kinase-dead mutants and PKA inhibitors, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"15069188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of autophosphorylation and catalytic sites, mass spectrometry identification of phosphorylation sites, whole-cell patch-clamp, Ca2+ influx assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with MS phosphosite identification and functional electrophysiology in one rigorous study\",\n      \"pmids\": [\"15781465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay (myosin IIA heavy chain phosphorylation), live-cell imaging, co-immunoprecipitation, overexpression/pharmacological inhibition of myosin II\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct substrate phosphorylation combined with cellular functional assays and pharmacology in one focused study\",\n      \"pmids\": [\"16407977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp of heterologously expressed and endogenous TRPM7, pharmacological manipulation of halide concentrations and kinase ATP-binding site\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological dissection, single lab, multiple conditions\",\n      \"pmids\": [\"23471296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"RNA interference, pulldown/GTPase activation assay (Rac/Cdc42), wound-healing assay, SLC41A2 rescue expression\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with GTPase pulldown and rescue experiments, single lab\",\n      \"pmids\": [\"21208190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"RNA interference (siRNA knockdown), migration/invasion assays, western blotting for pathway phosphorylation\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, siRNA knockdown with pathway readout, no mutagenesis or rescue\",\n      \"pmids\": [\"23353055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"TIRF Ca2+ fluorometry, TRPM7 channel inhibitor (waixenicin-A), knockdown, live-cell imaging\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with pharmacological and genetic inhibition, two orthogonal methods\",\n      \"pmids\": [\"24176224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional B cell-specific TRPM7 knockout mice, kinase-dead knock-in mice, in vitro rescue with Mg2+ supplementation, flow cytometry\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models (conditional KO and kinase-dead knock-in) with in vitro rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"29871911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Mast cell degranulation assays, histamine release measurement, TRPM7 kinase-dead knock-in mice (TRPM7KR) vs kinase-deletion mice (TRPM7+/ΔK), GPCR stimulation experiments\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse models (kinase-dead point mutation vs kinase-deletion), functional degranulation assays, dissection of channel vs kinase contributions\",\n      \"pmids\": [\"26660477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 kinase-dead mutant mice (Trpm7 R/R), T cell gut colonization assays, SMAD2 phosphorylation analysis, Th17/Treg differentiation experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic kinase-dead mouse model with mechanistic downstream (SMAD2) analysis and functional T cell assays\",\n      \"pmids\": [\"29203869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Trpm7 kinase-dead knock-in mice, platelet Ca2+ mobilization assays, phosphoprotein western blotting, in vivo arterial thrombosis and stroke models\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic kinase-dead mouse model with mechanistic phosphorylation readouts and in vivo disease models\",\n      \"pmids\": [\"29146750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7−/− DT40 B cells, kinase-deficient mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ flux measurements, CRAC current recordings\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout combined with kinase-dead mutants and pharmacological inhibition, multiple orthogonal approaches\",\n      \"pmids\": [\"28130783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7-deficient DT40 B cells, kinase-deficient mutant, antigen gathering/internalization assays, BCR signaling analysis, lipid metabolism profiling\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic models with functional B cell assays, PLCγ2 as kinase substrate proposed but not directly demonstrated by in vitro phosphorylation\",\n      \"pmids\": [\"29871912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological TRPM7 inhibition (NS8593), genome editing, RhoA activity assay, actin polymerization assay, MRTF-A localization imaging, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular and in vivo methods, but RhoA phosphorylation by TRPM7 kinase not directly confirmed by in vitro kinase assay\",\n      \"pmids\": [\"31844251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Multi-epitope affinity purification, high-resolution quantitative mass spectrometry, heterologous reconstitution co-immunoprecipitation, functional TRPM7 activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS-based native complex identification from brain tissue combined with functional reconstitution in heterologous system, multiple orthogonal methods\",\n      \"pmids\": [\"34766907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 kinase fragment nuclear localization (fractionation/imaging), chromatin immunoprecipitation (H3S10 phosphorylation at cytokine promoters), TRPM7-dependent Mg2+ influx assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear fractionation and ChIP combined with TRPM7-specific knockdown, single lab\",\n      \"pmids\": [\"34001887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological TRPM7 channel and kinase inhibition (TG100-115), murine neutrophils with genetic kinase ablation, transmigration assay, ROS measurement, Akt1/mTOR phosphorylation western blotting\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic kinase ablation confirmed by pharmacological inhibitor, functional neutrophil assays with pathway readout\",\n      \"pmids\": [\"33658993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA screen, perforated-patch electrophysiology, phagosomal pH measurements, genetically-encoded Ca2+ sensors in mice\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiology of endosomal current combined with in vivo Ca2+ imaging and functional phagosome maturation assays, multiple orthogonal methods\",\n      \"pmids\": [\"35680919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Palmitoylation assay, RUSH trafficking system (live imaging), zDHHC enzyme identification (co-expression/knockdown), Ca2+ flux measurement with non-palmitoylatable mutants\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct palmitoylation assay combined with live trafficking imaging and functional Ca2+ measurement with mutants, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36027648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, whole-cell and single-channel patch-clamp, molecular dynamics simulations\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional electrophysiology validated by MD simulations, structure-function relationship established\",\n      \"pmids\": [\"35389104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, functional electrophysiology, molecular dynamics simulations, inhibitor binding site mapping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with functional validation and MD simulations in one rigorous study\",\n      \"pmids\": [\"37156763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, metabolomics, TRPM7 genetic deletion, rescue with constitutively active CRTC2/CREB, Ca2+ imaging, xenograft models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with transcriptional rescue experiments and pathway dissection, single lab\",\n      \"pmids\": [\"36878949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genetically encoded Mg2+ reporter, co-immunoprecipitation (CNNM3/TRPM7/ARL15 complex), PRL-2 overexpression/knockdown, functional Mg2+ transport assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein complex co-IP with functional readout using Mg2+ reporter, single lab, multiple interactors tested\",\n      \"pmids\": [\"36972446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Kinase cross-phosphorylation assays, intracellular trafficking experiments, DT40 TRPM7-deficient complementation, surface labeling, TRPM6 kinase-dead mutant co-expression\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase assay plus functional cellular growth and trafficking experiments, single lab\",\n      \"pmids\": [\"24858416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 knockdown and pharmacological inhibition, PKCα-NOX4 co-immunoprecipitation, Ca2+ imaging, AAV9-mediated TRPM7 silencing in vivo, ferroptosis assays\",\n      \"journal\": \"Redox Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for PKCα/NOX4 complex with genetic and pharmacological TRPM7 inhibition, functional ferroptosis readout, single lab\",\n      \"pmids\": [\"35917680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 knockout/knockdown, multiple viral infection systems (pseudovirus and authentic virus), endosomal pH measurements, electrophysiology of TRPM7 currents\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function across multiple viral systems with mechanistic endosomal pH and electrophysiology measurements, multiple orthogonal approaches\",\n      \"pmids\": [\"39353909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, TRPM7 shRNA knockdown, pharmacological channel block (waixenicin A), Ca2+ imaging, neurite outgrowth assay\",\n      \"journal\": \"Molecular Neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and co-localization with functional knockdown and pharmacological evidence, single lab\",\n      \"pmids\": [\"25502295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp analysis, Ca2+ and Na+ imaging, site-directed mutagenesis (A931T, F971A, W972A), transfection of trigeminal ganglion neurons\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with electrophysiology in expression system and native neurons, single lab\",\n      \"pmids\": [\"36095216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 agonist treatment (clozapine, naltriben), Zn2+ imaging, autophagosome-lysosome fusion assay, co-immunoprecipitation (Sxt17/VAMP8), in vivo xenograft models\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with co-IP and Zn2+ imaging combined with in vivo validation, single lab\",\n      \"pmids\": [\"34752845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"TRPM7 kinase-deletion mice, cardiac histology, macrophage-fibroblast co-culture, calpain activity assay, intravital microscopy\",\n      \"journal\": \"Cardiovascular Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with co-culture mechanistic experiments, single lab\",\n      \"pmids\": [\"31250885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell patch-clamp, CaMKII inhibitor pharmacology (W-7, staurosporine, KN-93, CaMKII inhibitory peptide), Mg2+/Mg-ATP dialysis\",\n      \"journal\": \"American Journal of Physiology – Gastrointestinal and Liver Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological dissection of Ca2+/CaMKII pathway, single lab\",\n      \"pmids\": [\"19661151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological TRPM7 inhibition (NS8593), targeted genome editing, RhoA activity assay, MRTF-A nuclear localization imaging, actin polymerization assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches with signaling pathway readouts, single lab; RhoA direct phosphorylation by TRPM7 kinase inferred but not shown by direct in vitro assay\",\n      \"pmids\": [\"31844251\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPM7 is a ubiquitously expressed bifunctional 'chanzyme' comprising a divalent cation-permeable ion channel (conducting Ca2+, Mg2+, Zn2+ and other metals) and a C-terminal alpha-kinase domain; the channel is constitutively active but strongly inhibited by intracellular free Mg2+ binding to a conserved N1097 gate, by Mg·ATP/GTP, by PIP2 depletion downstream of PLC-coupled receptors, and by chloride/halides through the kinase ATP-binding site, while being potentiated by cAMP/PKA in a manner requiring an intact kinase domain; the kinase phosphorylates substrates including myosin IIA heavy chain, histone H3 (Ser10), annexin A1, and SMAD2, and is regulated by TRPM6 cross-phosphorylation; channel-mediated Mg2+ and Zn2+ fluxes control downstream effectors including calcineurin/CRTC2/CREB-driven glycolytic reprogramming, CaMKII-dependent Ca2+ inhibition, RhoA/actomyosin contractility, and endosomal acidification; the cleaved kinase fragment translocates to the nucleus to remodel chromatin; TRPM7 activity is further controlled by palmitoylation (by zDHHC17/zDHHC5) that governs trafficking between the cell surface and intracellular vesicles, and by its assembly into native TRPM7/CNNM/ARL15 ternary complexes that modulate its activity; collectively, TRPM7 integrates the metabolic/ionic state of the cell to regulate Mg2+ and Ca2+ homeostasis, cytoskeletal dynamics, immune cell function, phagosome maturation, cell survival, and gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#0, #23], 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 [#0, #2]. 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 [#3, #6]; its catalytic activity is dispensable for ion conduction, but the kinase domain is structurally required for channel assembly [#5]. 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 [#6, #8, #17]. 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 [#11, #12, #13, #14, #21, #29]. A nuclear kinase-cleaved fragment phosphorylates histone H3 Ser10 at inflammatory cytokine promoters, and channel-driven Ca2+ activates calcineurin/CRTC2/CREB to reprogram glycolysis [#19, #25]. 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 [#18, #22, #27]. No timeline discovery links TRPM7 to a defined Mendelian disease via causative mutation.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Electrophysiology in HEK/CHO overexpression and native cells, targeted DT-40 deletion (lethal), kinase-active-site mutagenesis and autophosphorylation\",\n      \"pmids\": [\"11385574\", \"11161216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether kinase catalysis vs domain structure underlies the channel requirement\", \"No structural basis for ion selectivity\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of kinase–PLC C2 domain, electrophysiology with receptor stimulation and PIP2 manipulation\",\n      \"pmids\": [\"11941371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of PIP2 binding to the channel not defined\", \"Did not separate PIP2 depletion from concurrent Ca2+ changes\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay with bacterially expressed kinase domain, substrate and cofactor titrations\",\n      \"pmids\": [\"14594813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not identified at this stage\", \"No structure of the active site\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patch-clamp with Gi/Gs receptor pharmacology, kinase-dead mutants, PKA inhibitors\",\n      \"pmids\": [\"15069188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKA phosphorylation site on TRPM7 not mapped\", \"Mechanism of kinase-domain requirement unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved that kinase catalysis is dispensable for conduction and Mg2+ inhibition while the kinase domain is structurally required, refining the channel–kinase coupling model.\",\n      \"evidence\": \"Autophosphorylation/catalytic-site mutagenesis, MS phosphosite mapping (Ser1511/Ser1567), patch-clamp and Ca2+ influx\",\n      \"pmids\": [\"15781465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the kinase domain supports assembly/localization not mechanistically defined\", \"Function of autophosphorylation sites unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro myosin IIA phosphorylation, live-cell imaging, Co-IP, myosin II pharmacology\",\n      \"pmids\": [\"16407977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify in vivo phosphostoichiometry\", \"Channel vs kinase contributions to each phenotype not fully separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a second feedback inhibition of the channel by cytosolic Ca2+ acting through CaMKII, adding Ca2+ sensing to the established Mg2+ regulation.\",\n      \"evidence\": \"Whole-cell patch-clamp with CaMKII inhibitor pharmacology and Mg·ATP dialysis in hepatocytes\",\n      \"pmids\": [\"19661151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CaMKII phosphorylation site on TRPM7 not mapped\", \"Single lab, native-current identity inferred\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that TRPM7-supplied Mg2+ is the critical downstream signal for Rac/Cdc42 activation and polarized migration, since SLC41A2 Mg2+ transport rescues the loss.\",\n      \"evidence\": \"RNAi, Rac/Cdc42 pulldown, wound-healing assay, SLC41A2 rescue\",\n      \"pmids\": [\"21208190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between Mg2+ and GTPase activation not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patch-clamp halide titration, siRNA with migration/invasion and pathway blotting, TIRF Ca2+ fluorometry with waixenicin-A\",\n      \"pmids\": [\"23471296\", \"23353055\", \"24176224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis/rescue for the MAPK link\", \"Mechanism coupling halide binding to gating not structurally resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"29871911\", \"24858416\", \"25502295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction and sites of TRPM6→TRPM7 phosphorylation not fully mapped in vivo\", \"Growth-cone work single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a channel-independent kinase function in mast cell exocytosis, showing the kinase sets sensitivity to intracellular Ca2+ and the degranulation rate.\",\n      \"evidence\": \"Kinase-dead knock-in vs kinase-deletion mice, degranulation and histamine release assays, GPCR stimulation\",\n      \"pmids\": [\"26660477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase substrate in the exocytic machinery not identified\", \"Link to Ca2+ sensitivity mechanism unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"29203869\", \"29146750\", \"28130783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase phosphorylation of SMAD2/PLC substrates not shown in vitro\", \"How kinase modulates SOCE mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed both channel and kinase functions are needed for B cell antigen internalization and lipid metabolism, nominating PLCγ2 as a candidate kinase target.\",\n      \"evidence\": \"TRPM7-deficient/kinase-dead DT40 B cells, antigen gathering/internalization, BCR signaling and lipid profiling\",\n      \"pmids\": [\"29871912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLCγ2 not validated as direct substrate by in vitro phosphorylation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"NS8593 inhibition, genome editing, RhoA activity and actin polymerization assays, MRTF-A imaging, xenografts\",\n      \"pmids\": [\"31844251\", \"31250885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RhoA phosphorylation by TRPM7 kinase not confirmed by direct in vitro assay\", \"Cardiac kinase-deletion phenotype mechanism (calpain) correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"34766907\", \"34001887\", \"34752845\", \"33658993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease generating the nuclear fragment not identified\", \"Functional consequence of CNNM/ARL15 binding on gating not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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'.\",\n      \"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\",\n      \"pmids\": [\"35389104\", \"36027648\", \"35680919\", \"35917680\", \"36095216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between palmitoylation and gating not mechanistically resolved\", \"A931T variant not linked to a defined human disease in the corpus\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"36878949\", \"36972446\", \"37156763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional target validation limited to single lab\", \"Inhibitor binding site not yet exploited therapeutically in the corpus\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a broadly protective antiviral role: TRPM7 channel countercurrent sustains V-ATPase-driven endosomal acidification required for entry of multiple low-pH enveloped viruses.\",\n      \"evidence\": \"TRPM7 KO/KD across pseudovirus and authentic virus systems, endosomal pH measurement, electrophysiology\",\n      \"pmids\": [\"39353909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal vs plasma-membrane channel pool not distinguished\", \"Therapeutic exploitation not tested in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 11, 21, 29]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 6, 13, 14]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 22, 29]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [22, 32]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [21, 29]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 25]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12, 13, 14, 20, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [17, 19, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 18, 26]}\n    ],\n    \"complexes\": [\n      \"TRPM7/CNNM/ARL15 ternary complex\"\n    ],\n    \"partners\": [\n      \"PLCB (PLC)\",\n      \"CNNM3\",\n      \"ARL15\",\n      \"TRPM6\",\n      \"MYH9 (myosin IIA)\",\n      \"ACTN1 (α-actinin-1)\",\n      \"ZDHHC17\",\n      \"ZDHHC5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}