{"gene":"TRPM7","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2001,"finding":"TRPM7 (LTRPC7) is a Mg·ATP- and Mg·GTP-regulated, voltage-independent divalent cation channel permeable to Ca2+ and Mg2+; intracellular Mg-nucleotides strongly suppress channel activity; targeted deletion in DT40 B cells is lethal, establishing TRPM7 as essential for cell viability.","method":"Heterologous expression in HEK-293 cells with whole-cell patch-clamp electrophysiology; targeted gene deletion in DT40 B cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — foundational electrophysiology + loss-of-function lethality, highly cited (807 citations)","pmids":["11385574"],"is_preprint":false},{"year":2004,"finding":"TRPM7 kinase phosphorylates annexin 1 at Ser5 within its N-terminal amphipathic alpha-helix in a Ca2+-stimulated manner, identifying annexin 1 as the first endogenous substrate of the TRPM7 kinase domain.","method":"In vitro kinase assay using TRPM7 kinase domain; phosphorylation confirmed in cell extracts overexpressing TRPM7; site identified by mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with site-specific mutagenesis","pmids":["15485879"],"is_preprint":false},{"year":2006,"finding":"TRPM7 activation by bradykinin leads to a Ca2+- and kinase-dependent interaction with the actomyosin cytoskeleton; TRPM7 kinase phosphorylates myosin IIA heavy chain; low-level overexpression increases intracellular Ca2+, promotes cell spreading, adhesion, focal adhesion formation, and kinase-dependently drives transformation of focal adhesions into podosomes.","method":"Live-cell imaging, Ca2+ imaging, kinase assays, co-immunoprecipitation, pharmacological inhibition of myosin II, overexpression/kinase-dead mutant analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, substrate identified, functional phenotype linked to kinase","pmids":["16407977"],"is_preprint":false},{"year":2006,"finding":"TRPM6 forms functional homomeric channels with distinct divalent cation permeability profile, pH sensitivity, and unitary conductance from TRPM7; TRPM6 and TRPM7 also form heteromeric TRPM6/7 complexes with intermediate properties; 2-APB differentially modulates TRPM6 (activation) vs. TRPM7 (inhibition) channels.","method":"Heterologous expression with whole-cell and single-channel patch-clamp electrophysiology; pharmacological profiling","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 — rigorous electrophysiology with multiple channel variants and pharmacological validation","pmids":["16636202"],"is_preprint":false},{"year":2009,"finding":"Virally mediated shRNA suppression of TRPM7 in hippocampal CA1 neurons in rats prevents delayed neuronal death after global brain ischemia without impairing LTP or memory under basal conditions, demonstrating TRPM7 mediates ischemia-induced neuronal death in vivo.","method":"In vivo viral vector shRNA delivery, electrophysiology (LTP), behavioral tasks, histology","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo loss-of-function with defined neuronal death phenotype and functional validation","pmids":["19734892"],"is_preprint":false},{"year":2011,"finding":"TRPM7 channel activity is inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) during phospholipase C-mediated signaling; regulation by Mg-nucleotides and cAMP/PKA requires a functional endogenous kinase domain; the kinase domain may autophosphorylate TRPM7.","method":"Patch-clamp electrophysiology, pharmacological manipulation, kinase-domain mutant analysis (reviewed/consolidated)","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2 — well-supported by electrophysiology across labs but presented as review compilation","pmids":["21290295"],"is_preprint":false},{"year":2011,"finding":"TRPM7 depletion by RNAi alters cell morphology, disrupts the cytoskeleton, and abolishes Rac and Cdc42 activation upon wound-healing stimulus, impairing polarized cell migration; Mg2+ transporter SLC41A2 expression rescues these defects, indicating Mg2+ is the critical ion mediating TRPM7 control of polarized movement.","method":"RNAi knockdown, pulldown GTPase activation assays (Rac/Cdc42), rescue with kinase-dead mutant and SLC41A2 overexpression, wound-healing assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal rescue experiments with orthogonal genetic tools establishing Mg2+ as the mechanistic effector","pmids":["21208190"],"is_preprint":false},{"year":2013,"finding":"TRPM7 channel activity is inhibited by intracellular chloride and bromide in synergy with Mg2+, acting through the ATP-binding site of the kinase domain; iodide is the strongest inhibitor at physiological Mg2+ and inhibits endogenous TRPM7-like currents in MCF-7 breast cancer cells.","method":"Whole-cell patch-clamp electrophysiology with intracellular halide dialysis, kinase-domain mutant analysis","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiology with mutagenesis identifying kinase ATP-binding site as regulatory locus","pmids":["23471296"],"is_preprint":false},{"year":2014,"finding":"TRPM7 kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner; the cleaved kinase fragments (M7CKs) translocate to the nucleus, bind chromatin-remodeling complexes including Polycomb group proteins, and phosphorylate histones (H3Ser10) at promoters of TRPM7-dependent genes; cytosolic free Zn2+ is TRPM7-dependent and regulates M7CK binding to zinc-finger transcription factors.","method":"Biochemical fractionation, co-immunoprecipitation, mass spectrometry, in vitro kinase assay on histones, Zn2+ imaging, transcriptomics","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (proteolysis, nuclear fractionation, in vitro kinase, imaging) in a single rigorous study","pmids":["24855944"],"is_preprint":false},{"year":2014,"finding":"TRPM7 channel activity produces localized Ca2+ microdomains ('sparks') at the ventral plasma membrane via extracellular Ca2+ influx; TRPM7 promotes invadosome formation independently of Ca2+ influx, instead acting through actomyosin contractility regulation.","method":"TIRF Ca2+ fluorometry, TRPM7 inhibitor (waixenicin A) application, automated Ca2+ spark analysis, invadosome quantification","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative imaging plus pharmacological dissection of Ca2+-dependent vs. independent functions","pmids":["24176224"],"is_preprint":false},{"year":2014,"finding":"TRPM7 channel activator naltriben acts through a site in or near the TRP domain; naltriben activates TRPM7 without prior Mg2+ depletion and even under low PIP2 conditions; kinase-domain and pore mutants indicate activation site is distinct from the kinase domain.","method":"Aequorin bioluminescence screen, whole-cell patch-clamp, TRPM7 domain mutant analysis","journal":"Pflugers Archiv","confidence":"High","confidence_rationale":"Tier 1 — screening plus mutagenesis localizing agonist binding site","pmids":["24633576"],"is_preprint":false},{"year":2014,"finding":"TRPM7 co-precipitates and co-localizes with F-actin and α-actinin-1 at neuronal growth cones; blocking TRPM7 channel conductance reduces Ca2+ influx and accelerates axonal polarization and outgrowth, demonstrating that TRPM7-mediated Ca2+ influx inhibits axonal outgrowth via the F-actin/α-actinin-1 complex.","method":"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, waixenicin A pharmacological blockade, Ca2+ imaging","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 — co-IP combined with functional rescue and Ca2+ imaging","pmids":["25502295"],"is_preprint":false},{"year":2016,"finding":"TRPM7 kinase activity (not channel activity) regulates mast cell degranulation and histamine release; TRPM7 kinase modulates sensitivity to intracellular Ca2+ and extracellular Mg2+ during IgE-dependent exocytosis, and affects granule mobility/contents.","method":"Comparison of TRPM7+/ΔK and TRPM7KR (kinase-dead point mutant) mouse mast cells; exocytosis assays, histamine release measurements","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic separation of channel and kinase activities in mouse models with specific functional readout","pmids":["26660477"],"is_preprint":false},{"year":2016,"finding":"Aldosterone increases TRPM7 plasma membrane expression and current through a mineralocorticoid receptor (MR)-dependent genomic cascade involving SGK1; this upregulation requires a functioning TRPM7 α-kinase domain, as kinase-dead K1648R-TRPM7 is unresponsive to aldosterone.","method":"Whole-cell patch-clamp, cell-surface biotinylation, pharmacological blockade of MR (eplerenone) and SGK1 (GSK-650394), kinase-dead mutant expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — electrophysiology combined with surface protein quantification and mutant analysis","pmids":["27466368"],"is_preprint":false},{"year":2016,"finding":"The coiled-coil domain of TRPM7 is required for channel regulation by intracellular Mg2+ and Mg·ATP; C-terminal truncation mutants of zebrafish TRPM7 losing the coiled-coil domain show altered Mg-nucleotide sensitivity.","method":"C-terminal truncation mutant analysis by whole-cell patch-clamp electrophysiology in heterologous expression system","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — domain deletion mutagenesis with direct electrophysiological functional readout","pmids":["27628598"],"is_preprint":false},{"year":2017,"finding":"TRPM7 kinase activity (not channel activity itself) regulates store-operated calcium entry (SOCE)/CRAC currents in B lymphocytes; TRPM7 channel activity is required to maintain endoplasmic reticulum Ca2+ store levels at rest and for refilling after Ca2+ signaling events.","method":"TRPM7-/- DT40 B cells, kinase-deficient TRPM7 mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ imaging, patch-clamp of ICRAC","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological separation of channel/kinase roles with electrophysiology and Ca2+ imaging","pmids":["28130783"],"is_preprint":false},{"year":2017,"finding":"A point mutation in the TRPM7 kinase domain deleting kinase activity in mice causes impaired PIP2 metabolism and reduced Ca2+ mobilization in platelets in response to GPVI, CLEC-2, and PAR receptors; altered Syk and phospholipase Cγ2/β3 phosphorylation accounts for the defect; TRPM7 kinase-dead mice are protected from arterial thrombosis and ischemic stroke.","method":"Kinase-dead knock-in mice (Trpm7R/R), platelet activation assays, phosphoproteomics, in vivo thrombosis and stroke models","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse model with defined signaling mechanism and in vivo disease phenotype","pmids":["29146750"],"is_preprint":false},{"year":2017,"finding":"TRPM7 kinase domain is essential for normal synapse density; re-expression of the α-kinase domain alone (without channel) rescues synapse density, plasticity, and memory in TRPM7 conditional knockout mice, likely through kinase-mediated phosphorylation of cofilin.","method":"Hippocampal-specific TRPM7 knockdown/conditional KO in mice, electrophysiology (LTP), behavioral tests, rescue with α-kinase domain construct, cofilin phosphorylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — domain-specific rescue in vivo with multiple functional readouts","pmids":["29924992"],"is_preprint":false},{"year":2017,"finding":"TRPM7 kinase activity in ameloblasts phosphorylates CREB directly (shown by co-immunoprecipitation); kinase-inactive knock-in mice exhibit defective ameloblast differentiation with impaired phosphorylation of Smad1/5/9, p38, and CREB at the pre-secretory stage, demonstrating kinase-dependent control of tooth enamel formation.","method":"TRPM7 kinase-dead (KR) knock-in mice, immunoprecipitation of CREB-TRPM7 complex, phosphoprotein analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse model + co-IP identifying CREB as direct kinase substrate","pmids":["29273814"],"is_preprint":false},{"year":2018,"finding":"TRPM7 channel and kinase both contribute to antigen gathering and BCR signaling in B cells; TRPM7-deficient or kinase-deficient DT40 B cells show defective antigen gathering, prolonged BCR signaling, and altered lipid metabolism; blocking TRPM7 function impairs antigen internalization and presentation to T cells.","method":"TRPM7-/- and kinase-dead B cell lines, BCR signaling assays, antigen internalization and presentation assays, lipid metabolism analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — genetic separation of channel and kinase functions with functional cellular readout","pmids":["29871912"],"is_preprint":false},{"year":2018,"finding":"TRPM7 ion channel activity (not kinase activity) is required for B cell development; mice lacking TRPM7 in B cells exhibit developmental block at the pro-B cell stage; high extracellular Mg2+ partially rescues TRPM7-deficient B cell development in vitro.","method":"B cell-specific TRPM7 knockout mice, flow cytometry of B cell developmental stages, Mg2+ rescue experiments in vitro","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO mouse with defined developmental block and Mg2+ rescue","pmids":["29871911"],"is_preprint":false},{"year":2019,"finding":"TRPM7 signaling regulates RhoA activity and actin polymerization, MRTF-A–Filamin A complex formation, and MRTF-A/SRF-dependent gene expression through Mg2+ influx via the channel and phosphorylation of RhoA by TRPM7 kinase.","method":"TRPM7 pharmacological inhibition (NS8593), CRISPR knockout, RhoA activity assays, actin polymerization assays, co-immunoprecipitation of MRTF-A/Filamin A","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological tools combined with biochemical pathway dissection","pmids":["31844251"],"is_preprint":false},{"year":2021,"finding":"Native TRPM7 channels in rodent brain form high-molecular-weight multi-protein complexes containing CNNM1-4 metal transporter proteins and the small GTPase ARL15; reconstitution experiments confirm TRPM7/CNNM/ARL15 ternary complex formation, which specifically impacts TRPM7 channel activity.","method":"Multi-epitope affinity purification from native brain tissue, quantitative mass spectrometry, heterologous reconstitution, patch-clamp electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — native complex purification from brain + MS + reconstitution + electrophysiology","pmids":["34766907"],"is_preprint":false},{"year":2021,"finding":"CNNM proteins selectively bind to and stimulate TRPM7 channel-mediated divalent cation entry; CNNMs require the TRPM7 channel pore for divalent uptake; PRL phosphatases stimulate TRPM7-dependent divalent entry via CNNMs; CNNMs also possess separate TRPM7-independent Mg2+ efflux activity.","method":"CNNM knockouts in HEK-293 cells, pore-dead TRPM7 mutants, whole-cell patch-clamp, divalent cation uptake assays, co-expression studies","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 — KO cells, pore mutants, electrophysiology, and functional divalent uptake assays","pmids":["34928937"],"is_preprint":false},{"year":2021,"finding":"TRPM7 kinase cleaved fragments (M7CKs) accumulate in macrophage nuclei upon Mg2+ stimulation and phosphorylate Histone H3 at serine 10 at promoters of inflammatory cytokines, creating a pro-osteogenic immune microenvironment.","method":"Nuclear fractionation, ChIP, TRPM7-dependent H3S10 phosphorylation assays, macrophage Mg2+ influx measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP and nuclear fractionation demonstrating kinase-dependent histone modification in primary immune cells","pmids":["34001887"],"is_preprint":false},{"year":2021,"finding":"TRPM7 kinase activity regulates neutrophil transmigration along CXCL8 gradient and ROS production in response to LPS; TRPM7 kinase affects Akt1/mTOR signaling in neutrophils, controlling transmigration and effector function.","method":"Pharmacological TRPM7 channel and kinase inhibitors, murine neutrophils with genetic kinase ablation, transwell migration assay, ROS production assay, Akt/mTOR signaling analysis","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic kinase ablation confirmed by pharmacology with defined signaling pathway","pmids":["33658993"],"is_preprint":false},{"year":2022,"finding":"Intracellular Mg2+ binds to a conserved N1097 inter-subunit site in the lower channel gate of TRPM7, stabilizing the closed state; removal of Mg2+ from this site favors channel opening, establishing the structural mechanism of Mg2+-dependent TRPM7 inhibition.","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 — mutagenesis at identified gate residue with single-channel electrophysiology and MD simulation validation","pmids":["35389104"],"is_preprint":false},{"year":2022,"finding":"TRPM7 is required for phagosome maturation during efferocytosis in macrophages; TRPM7 mediates a pH-activated cationic current that sustains phagosomal acidification; TRPM7-dependent peri-phagosomal Ca2+ signals are necessary for phagosome maturation.","method":"siRNA screen, perforated patch electrophysiology, genetically-encoded Ca2+ sensor in mice, phagosome acidification and cargo digestion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — siRNA screen hit validated by in vivo Ca2+ sensor and direct electrophysiology of phagosomal current","pmids":["35680919"],"is_preprint":false},{"year":2022,"finding":"TrpM7 is palmitoylated at a cysteine cluster at the C-terminal end of its Trp domain by zDHHC17 (Golgi) and zDHHC5 (surface membrane); palmitoylation controls TrpM7 exit from the ER and distribution between cell surface and intracellular vesicles; non-palmitoylated TrpM7 is sequestered intracellularly and shows significantly reduced transmembrane Ca2+ uptake.","method":"RUSH trafficking system, palmitoylation site mutagenesis, zDHHC knockdown/identification, Ca2+ uptake assay","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1–2 — direct identification of palmitoyl-transferases, trafficking assay, and functional Ca2+ transport measurement","pmids":["36027648"],"is_preprint":false},{"year":2022,"finding":"A TRPM7 gain-of-function mutation (A931T) in transmembrane domain S3 generates an omega current carried by Na+ that is insensitive to the pore blocker Gd3+; expression of A931T in trigeminal ganglion neurons lowers current threshold, resting membrane potential, and increases evoked firing, suggesting this mutation underlies pain in familial trigeminal neuralgia.","method":"Whole-exome sequencing, patch-clamp analysis of mutant channels, Na+/Ca2+ imaging, transfection of TG neurons with A931T","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — electrophysiological characterization in HEK and native neurons with mutagenesis identifying mechanism","pmids":["36095216"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of TRPM7 reveal two distinct activation mechanisms: gain-of-function mutation and the agonist naltriben show different conformational dynamics and domain involvement; a binding site for potent selective inhibitors was identified in the closed state; inhibitors act by stabilizing the TRPM7 closed state.","method":"Cryo-EM structure determination, functional mutagenesis, molecular dynamics simulations, electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with mutagenesis and MD simulations providing atomic-level mechanism","pmids":["37156763"],"is_preprint":false},{"year":2023,"finding":"TRPM7 channel transcriptionally regulates glycolytic enzyme SLC2A3/GLUT3 via Ca2+ influx-induced calcineurin activation, acting through CRTC2 and CREB as downstream effectors; TRPM7 deletion suppresses cancer cell glycolysis and xenograft tumor growth, and inhibits postnatal retinal angiogenesis.","method":"RNA-seq, metabolomics, TRPM7 knockout cells and mice, calcineurin inhibition, CRTC2/CREB rescue experiments, in vivo tumor and retinal angiogenesis models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — multi-omics plus genetic rescue experiments defining complete signaling axis","pmids":["36878949"],"is_preprint":false},{"year":2023,"finding":"PRL-1/2 phosphatases enhance TRPM7 Mg2+ channel activity by preventing CNNM3 interaction with TRPM7; ARL15 (small GTPase) increases CNNM3/TRPM7 complex formation to reduce TRPM7 activity; at low cellular Mg2+, CNNM3-TRPM7 interaction is reduced in a PRL-dependent manner, coupling Mg2+ sensing to TRPM7 function.","method":"Genetically-encoded intracellular Mg2+ reporter, co-immunoprecipitation, TRPM7 activity assays, PRL-1/2 KO cells","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — novel Mg2+ reporter plus co-IP and genetic KO establishing regulatory complex dynamics","pmids":["36972446"],"is_preprint":false},{"year":2014,"finding":"TRPM6 kinase cross-phosphorylates TRPM7 on serine residues (but not vice versa), alters TRPM7 intracellular trafficking, and inhibits TRPM7-dependent cell growth under hypomagnesic conditions in a kinase-activity-dependent manner.","method":"Kinase phosphorylation assays, TRPM7 trafficking analysis in HEK-293 and DT40 cells, kinase-dead TRPM6 mutant complementation, cell growth assays","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — direct kinase substrate identification combined with trafficking and growth assays using kinase-dead mutants","pmids":["24858416"],"is_preprint":false},{"year":2021,"finding":"TRPM7 channel stimulation by clozapine or naltriben mediates Zn2+ release from intracellular Zn2+-accumulating vesicles (where TRPM7 localizes) into the cytosol; this Zn2+ release disrupts autophagosome-lysosome fusion by interfering with Sxt17-VAMP8 interaction, arresting autophagy.","method":"Zn2+ imaging, TRPM7 pharmacological activation, co-immunoprecipitation of Sxt17-VAMP8, autophagy flux assays, intracellular TRPM7 localization","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanism defined by imaging and co-IP but in single study with pharmacological tools","pmids":["34752845"],"is_preprint":false},{"year":2020,"finding":"TRPM7 kinase deficiency (TRPM7+/Δkinase mice) causes cardiac hypertrophy, fibrosis, and inflammation; reduced cardiac Mg2+ (not Ca2+), upregulation of calpain, and increased pro-fibrotic cytokine signaling (SMAD3, TGFβ) are downstream consequences; TRPM7+/Δkinase macrophages drive cardiac fibroblast activation.","method":"TRPM7 kinase-deficient mice, cardiac histology, cytokine profiling, macrophage-fibroblast co-culture, intracellular ion measurements, intra-vital microscopy","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — defined mouse genetic model with multiple mechanistic readouts including ion measurements and co-culture","pmids":["31250885"],"is_preprint":false}],"current_model":"TRPM7 is a ubiquitous plasma membrane 'chanzyme' consisting of a Mg2+- and Ca2+-permeable divalent cation channel (also conducting Zn2+, Mn2+, and monovalent ions) whose activity is constitutively suppressed by intracellular Mg2+ binding to a conserved lower-gate site (N1097) and by Mg·ATP/Mg·GTP; palmitoylation at its Trp domain controls trafficking between the cell surface and intracellular vesicles; the channel is flanked by a C-terminal α-kinase that is proteolytically released, translocates to the nucleus, and phosphorylates histones (H3S10) to regulate gene expression, while also phosphorylating cytoplasmic substrates including annexin 1, myosin IIA heavy chain, cofilin, RhoA, and CREB to control actomyosin contractility, cell adhesion, migration, and synaptic density; TRPM7 function is additionally regulated by its assembly into native complexes with CNNM1-4 metal transporters and ARL15, which modulate channel activity; collectively the channel and kinase activities regulate cellular Mg2+/Ca2+/Zn2+ homeostasis, store-operated Ca2+ entry, B cell development, mast cell degranulation, neutrophil transmigration, macrophage efferocytosis, and platelet activation, while loss of TRPM7 expression or activity causes cell death under Mg2+-deplete conditions and mediates ischemic neuronal death in vivo."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that TRPM7 constitutes a novel class of Mg·ATP-regulated divalent cation channel essential for cell viability resolved the molecular identity of the ubiquitous Mg²⁺-inhibited current and demonstrated that channel loss is cell-lethal.","evidence":"Heterologous expression with patch-clamp in HEK-293 and targeted gene deletion in DT40 B cells","pmids":["11385574"],"confidence":"High","gaps":["Structural basis of Mg·ATP inhibition unresolved","Channel vs. kinase contribution to lethality not separated"]},{"year":2004,"claim":"Identification of annexin 1 and subsequently myosin IIA heavy chain as direct TRPM7 kinase substrates established that the kinase domain has autonomous signaling functions beyond ion conduction, linking it to Ca²⁺-dependent membrane dynamics and actomyosin contractility.","evidence":"In vitro kinase assays with site-directed mutagenesis (annexin 1 Ser5); co-IP plus kinase-dead mutant analysis and live-cell imaging for myosin IIA","pmids":["15485879","16407977"],"confidence":"High","gaps":["Full kinase substrate repertoire unknown","In vivo relevance of annexin 1 phosphorylation not tested"]},{"year":2006,"claim":"Demonstration that TRPM6 and TRPM7 form distinct homomeric and heteromeric channels with different permeation and pharmacological profiles clarified their non-redundant physiological roles in divalent cation homeostasis.","evidence":"Whole-cell and single-channel patch-clamp of homo- and heteromeric channels with pharmacological profiling (2-APB)","pmids":["16636202"],"confidence":"High","gaps":["Stoichiometry and assembly rules of heteromeric channels not determined","Tissue-specific ratio of homo- vs. heteromeric channels unknown"]},{"year":2009,"claim":"Showing that hippocampal TRPM7 knockdown prevents delayed neuronal death after global ischemia without affecting basal synaptic function established TRPM7 as a mediator of ischemic neuronal injury in vivo.","evidence":"Viral shRNA delivery to rat CA1 neurons, electrophysiology (LTP), behavioral testing, histology","pmids":["19734892"],"confidence":"High","gaps":["Downstream death pathway (Ca²⁺ vs. Zn²⁺ overload) not delineated","Kinase vs. channel contribution to ischemic death not separated"]},{"year":2011,"claim":"Rescue of TRPM7-knockdown migration defects by the Mg²⁺ transporter SLC41A2 identified Mg²⁺ as the critical effector ion through which TRPM7 controls Rac/Cdc42 activation and polarized cell migration, separating Mg²⁺-dependent from Ca²⁺-dependent channel functions.","evidence":"siRNA knockdown with GTPase activation pulldowns, rescue with kinase-dead TRPM7 and SLC41A2 overexpression, wound-healing assays","pmids":["21208190"],"confidence":"High","gaps":["Direct Mg²⁺-sensing mechanism linking Rac/Cdc42 activation not identified","In vivo validation in migratory cell types lacking"]},{"year":2014,"claim":"Discovery that the TRPM7 kinase domain is proteolytically cleaved, translocates to the nucleus, and phosphorylates histone H3 at Ser10 at target promoters revealed an unanticipated mechanism by which an ion channel directly regulates chromatin and gene expression.","evidence":"Biochemical fractionation, co-IP with Polycomb proteins, mass spectrometry, in vitro histone kinase assay, Zn²⁺ imaging, transcriptomics","pmids":["24855944"],"confidence":"High","gaps":["Protease responsible for cleavage not identified","Genome-wide map of H3S10ph targets incomplete","Regulation of cleavage kinetics unknown"]},{"year":2014,"claim":"TRPM6 kinase was found to cross-phosphorylate TRPM7 (but not vice versa), altering TRPM7 trafficking and growth under hypomagnesemia, establishing a directional kinase crosstalk between the two chanzymes.","evidence":"Kinase assays, trafficking analysis, kinase-dead TRPM6 complementation in HEK-293 and DT40 cells","pmids":["24858416"],"confidence":"High","gaps":["Phosphorylation sites on TRPM7 not mapped","Physiological relevance in epithelial Mg²⁺ transport not confirmed in vivo"]},{"year":2016,"claim":"Genetic separation of kinase and channel functions in mouse mast cells showed that kinase activity (not channel conductance) controls IgE-dependent degranulation and histamine release by modulating sensitivity to intracellular Ca²⁺ and extracellular Mg²⁺.","evidence":"Comparison of TRPM7+/ΔK and kinase-dead (KR) mouse mast cells, exocytosis and histamine release assays","pmids":["26660477"],"confidence":"High","gaps":["Direct kinase substrate in mast cell exocytic machinery not identified"]},{"year":2017,"claim":"In vivo studies using kinase-dead knock-in mice revealed that TRPM7 kinase controls platelet activation via Syk/PLCγ phosphorylation and PIP2 metabolism, protecting against arterial thrombosis and ischemic stroke, and independently maintains synapse density through cofilin phosphorylation.","evidence":"Trpm7R/R kinase-dead mice with platelet assays, phosphoproteomics, in vivo thrombosis models; hippocampal conditional KO with α-kinase rescue, LTP, and behavioral tests","pmids":["29146750","29924992"],"confidence":"High","gaps":["Full phosphoproteomic substrate spectrum in platelets and neurons not defined","Whether kinase effects on cofilin are direct or via intermediate kinases unclear"]},{"year":2018,"claim":"B cell-specific TRPM7 knockout revealed that channel-mediated Mg²⁺ influx is essential for B cell development at the pro-B stage, while both channel and kinase contribute to BCR signaling, antigen gathering, and presentation to T cells.","evidence":"B cell-specific KO mice, flow cytometry of developmental stages, Mg²⁺ rescue, kinase-dead B cell lines with BCR signaling and antigen presentation assays","pmids":["29871911","29871912"],"confidence":"High","gaps":["How Mg²⁺ influx specifically permits pro-B to pre-B transition is mechanistically unresolved"]},{"year":2019,"claim":"TRPM7 was shown to control the RhoA–actin–MRTF-A/SRF transcriptional axis through both Mg²⁺ influx and direct RhoA phosphorylation by the kinase, connecting channel activity to gene expression programs governing cytoskeletal remodeling.","evidence":"CRISPR KO, pharmacological inhibition (NS8593), RhoA activity assays, co-IP of MRTF-A/Filamin A","pmids":["31844251"],"confidence":"High","gaps":["RhoA phosphorylation site by TRPM7 kinase not mapped","Relative contribution of Mg²⁺ vs. kinase in different cell types unknown"]},{"year":2021,"claim":"Purification of native TRPM7 complexes from brain identified CNNM1–4 and ARL15 as stable partners that modulate channel activity, and subsequent studies showed PRL phosphatases tune this complex to couple cellular Mg²⁺ sensing to TRPM7 function.","evidence":"Multi-epitope affinity purification, quantitative mass spectrometry, reconstitution with patch-clamp; genetically encoded Mg²⁺ reporter, PRL-1/2 KO cells, co-IP","pmids":["34766907","34928937","36972446"],"confidence":"High","gaps":["Structural basis of CNNM–TRPM7 interface unknown","Whether CNNM regulation of TRPM7 operates identically in all tissues not tested"]},{"year":2022,"claim":"Identification of N1097 as the intracellular Mg²⁺-binding site in the lower channel gate provided the first structural explanation for how physiological Mg²⁺ suppresses TRPM7 opening.","evidence":"Site-directed mutagenesis, single-channel electrophysiology, molecular dynamics simulations","pmids":["35389104"],"confidence":"High","gaps":["Full-length high-resolution structure with Mg²⁺ at this site not yet available","Cooperativity among four subunit gate sites not characterized"]},{"year":2022,"claim":"Demonstrating that TRPM7 localizes to phagosomes, conducts a pH-activated cationic current, and sustains phagosomal acidification established a previously unknown role for TRPM7 in macrophage efferocytosis.","evidence":"siRNA screen, perforated patch electrophysiology, genetically encoded phagosomal Ca²⁺ sensor in mice, cargo digestion assays","pmids":["35680919"],"confidence":"High","gaps":["Identity of the pH sensor within TRPM7 not determined","Whether phagosomal TRPM7 is palmitoylation-dependent not tested"]},{"year":2022,"claim":"Discovery that palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls TRPM7 ER exit and surface residence revealed a post-translational trafficking switch regulating channel availability.","evidence":"RUSH trafficking system, palmitoylation-site mutagenesis, zDHHC knockdown, Ca²⁺ uptake assays","pmids":["36027648"],"confidence":"High","gaps":["Dynamic regulation of palmitoylation/depalmitoylation cycle not characterized","Which thioesterase depalmitoylates TRPM7 unknown"]},{"year":2022,"claim":"A TRPM7 gain-of-function mutation (A931T) was linked to familial trigeminal neuralgia by generating a gating-pore omega current that lowers neuronal firing threshold, providing the first Mendelian disease association for TRPM7.","evidence":"Whole-exome sequencing, patch-clamp of mutant channels in HEK-293 and trigeminal ganglion neurons, Na⁺/Ca²⁺ imaging","pmids":["36095216"],"confidence":"High","gaps":["Penetrance and prevalence in other trigeminal neuralgia cohorts not established","Therapeutic targetability of the omega current not tested"]},{"year":2023,"claim":"Cryo-EM structures of TRPM7 in closed, agonist-bound, and gain-of-function states delineated two distinct activation mechanisms and identified a selective-inhibitor binding pocket, providing an atomic framework for drug design.","evidence":"Cryo-EM, functional mutagenesis, molecular dynamics simulations, electrophysiology","pmids":["37156763"],"confidence":"High","gaps":["Structure of TRPM7 in complex with CNNM/ARL15 not resolved","Kinase-domain conformation relative to channel in full-length structure not fully defined"]},{"year":null,"claim":"Key unresolved questions include the identity of the protease that cleaves the kinase domain, the full substrate repertoire of the kinase in different tissues, the structural basis of the TRPM7–CNNM–ARL15 regulatory complex, and whether channel and kinase activities can be therapeutically targeted independently.","evidence":"","pmids":[],"confidence":"High","gaps":["Protease identity for kinase cleavage unknown","Tissue-specific kinase substrate mapping incomplete","No TRPM7–CNNM–ARL15 co-structure available","Selective kinase-only or channel-only inhibitors not yet validated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,8,12,16,17,18,21,24,25]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,8,17,18,33]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,3,15,22,23,26,27]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,13,28]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,24]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[28,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,13,16,21,25,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,19,20,25,27]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,6,22,23,26]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,21,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4]}],"complexes":["TRPM7-CNNM-ARL15","TRPM6/TRPM7 heteromer"],"partners":["CNNM1","CNNM3","ARL15","TRPM6","ACTN1","MYH9","ANXA1","ZDHHC17"],"other_free_text":[]},"mechanistic_narrative":"TRPM7 is a ubiquitously expressed bifunctional 'chanzyme' that couples a divalent cation-permeable channel (Ca²⁺, Mg²⁺, Zn²⁺) to a C-terminal α-kinase domain, integrating ion transport with phosphorylation-dependent signaling to control cell viability, migration, immune cell function, and gene expression. The channel is constitutively suppressed by intracellular Mg²⁺ binding at a conserved lower-gate residue (N1097) and by Mg·ATP, requires PIP2, and is regulated by assembly into native complexes with CNNM1–4 metal transporters and the small GTPase ARL15, which tune divalent cation entry; palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls surface trafficking [PMID:35389104, PMID:34766907, PMID:36027648, PMID:11385574]. The α-kinase domain undergoes proteolytic cleavage, and the released fragment translocates to the nucleus where it phosphorylates histone H3 at Ser10 at target-gene promoters in association with Polycomb complexes, while cytoplasmic substrates including myosin IIA heavy chain, annexin 1, cofilin, RhoA, and CREB control actomyosin contractility, cell migration, synapse density, mast cell degranulation, platelet activation, and neutrophil transmigration [PMID:24855944, PMID:16407977, PMID:29924992, PMID:26660477, PMID:29146750]. A gain-of-function A931T mutation generating a gating-pore omega current in TRPM7 causes familial trigeminal neuralgia, and cryo-EM structures have delineated distinct activation mechanisms by agonists versus gain-of-function mutations and identified a selective-inhibitor binding pocket in the closed state [PMID:36095216, PMID:37156763]."},"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 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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":"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":24,"is_preprint":false},{"pmid":"29273814","id":"PMC_29273814","title":"The crucial role of the TRPM7 kinase domain in the early stage of amelogenesis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29273814","citation_count":24,"is_preprint":false},{"pmid":"34752845","id":"PMC_34752845","title":"Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy.","date":"2021","source":"Cancer 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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":22,"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":"27628598","id":"PMC_27628598","title":"The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27628598","citation_count":22,"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":"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":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":"36027648","id":"PMC_36027648","title":"Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7.","date":"2022","source":"Cell 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agents selectively acting on the channel moieties of TRPM6 and TRPM7.","date":"2022","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/36030694","citation_count":21,"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":20,"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":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 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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":19,"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":17,"is_preprint":false},{"pmid":"27466368","id":"PMC_27466368","title":"Aldosterone Upregulates Transient Receptor Potential Melastatin 7 (TRPM7).","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27466368","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46700,"output_tokens":8518,"usd":0.133935},"stage2":{"model":"claude-opus-4-6","input_tokens":12364,"output_tokens":4598,"usd":0.265155},"total_usd":0.39909,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"TRPM7 (LTRPC7) is a Mg·ATP- and Mg·GTP-regulated, voltage-independent divalent cation channel permeable to Ca2+ and Mg2+; intracellular Mg-nucleotides strongly suppress channel activity; targeted deletion in DT40 B cells is lethal, establishing TRPM7 as essential for cell viability.\",\n      \"method\": \"Heterologous expression in HEK-293 cells with whole-cell patch-clamp electrophysiology; targeted gene deletion in DT40 B cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational electrophysiology + loss-of-function lethality, highly cited (807 citations)\",\n      \"pmids\": [\"11385574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRPM7 kinase phosphorylates annexin 1 at Ser5 within its N-terminal amphipathic alpha-helix in a Ca2+-stimulated manner, identifying annexin 1 as the first endogenous substrate of the TRPM7 kinase domain.\",\n      \"method\": \"In vitro kinase assay using TRPM7 kinase domain; phosphorylation confirmed in cell extracts overexpressing TRPM7; site identified by mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with site-specific mutagenesis\",\n      \"pmids\": [\"15485879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRPM7 activation by bradykinin leads to a Ca2+- and kinase-dependent interaction with the actomyosin cytoskeleton; TRPM7 kinase phosphorylates myosin IIA heavy chain; low-level overexpression increases intracellular Ca2+, promotes cell spreading, adhesion, focal adhesion formation, and kinase-dependently drives transformation of focal adhesions into podosomes.\",\n      \"method\": \"Live-cell imaging, Ca2+ imaging, kinase assays, co-immunoprecipitation, pharmacological inhibition of myosin II, overexpression/kinase-dead mutant analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, substrate identified, functional phenotype linked to kinase\",\n      \"pmids\": [\"16407977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRPM6 forms functional homomeric channels with distinct divalent cation permeability profile, pH sensitivity, and unitary conductance from TRPM7; TRPM6 and TRPM7 also form heteromeric TRPM6/7 complexes with intermediate properties; 2-APB differentially modulates TRPM6 (activation) vs. TRPM7 (inhibition) channels.\",\n      \"method\": \"Heterologous expression with whole-cell and single-channel patch-clamp electrophysiology; pharmacological profiling\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous electrophysiology with multiple channel variants and pharmacological validation\",\n      \"pmids\": [\"16636202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Virally mediated shRNA suppression of TRPM7 in hippocampal CA1 neurons in rats prevents delayed neuronal death after global brain ischemia without impairing LTP or memory under basal conditions, demonstrating TRPM7 mediates ischemia-induced neuronal death in vivo.\",\n      \"method\": \"In vivo viral vector shRNA delivery, electrophysiology (LTP), behavioral tasks, histology\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo loss-of-function with defined neuronal death phenotype and functional validation\",\n      \"pmids\": [\"19734892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPM7 channel activity is inhibited by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) during phospholipase C-mediated signaling; regulation by Mg-nucleotides and cAMP/PKA requires a functional endogenous kinase domain; the kinase domain may autophosphorylate TRPM7.\",\n      \"method\": \"Patch-clamp electrophysiology, pharmacological manipulation, kinase-domain mutant analysis (reviewed/consolidated)\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — well-supported by electrophysiology across labs but presented as review compilation\",\n      \"pmids\": [\"21290295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPM7 depletion by RNAi alters cell morphology, disrupts the cytoskeleton, and abolishes Rac and Cdc42 activation upon wound-healing stimulus, impairing polarized cell migration; Mg2+ transporter SLC41A2 expression rescues these defects, indicating Mg2+ is the critical ion mediating TRPM7 control of polarized movement.\",\n      \"method\": \"RNAi knockdown, pulldown GTPase activation assays (Rac/Cdc42), rescue with kinase-dead mutant and SLC41A2 overexpression, wound-healing assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal rescue experiments with orthogonal genetic tools establishing Mg2+ as the mechanistic effector\",\n      \"pmids\": [\"21208190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPM7 channel activity is inhibited by intracellular chloride and bromide in synergy with Mg2+, acting through the ATP-binding site of the kinase domain; iodide is the strongest inhibitor at physiological Mg2+ and inhibits endogenous TRPM7-like currents in MCF-7 breast cancer cells.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology with intracellular halide dialysis, kinase-domain mutant analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiology with mutagenesis identifying kinase ATP-binding site as regulatory locus\",\n      \"pmids\": [\"23471296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM7 kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner; the cleaved kinase fragments (M7CKs) translocate to the nucleus, bind chromatin-remodeling complexes including Polycomb group proteins, and phosphorylate histones (H3Ser10) at promoters of TRPM7-dependent genes; cytosolic free Zn2+ is TRPM7-dependent and regulates M7CK binding to zinc-finger transcription factors.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, mass spectrometry, in vitro kinase assay on histones, Zn2+ imaging, transcriptomics\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (proteolysis, nuclear fractionation, in vitro kinase, imaging) in a single rigorous study\",\n      \"pmids\": [\"24855944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM7 channel activity produces localized Ca2+ microdomains ('sparks') at the ventral plasma membrane via extracellular Ca2+ influx; TRPM7 promotes invadosome formation independently of Ca2+ influx, instead acting through actomyosin contractility regulation.\",\n      \"method\": \"TIRF Ca2+ fluorometry, TRPM7 inhibitor (waixenicin A) application, automated Ca2+ spark analysis, invadosome quantification\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative imaging plus pharmacological dissection of Ca2+-dependent vs. independent functions\",\n      \"pmids\": [\"24176224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM7 channel activator naltriben acts through a site in or near the TRP domain; naltriben activates TRPM7 without prior Mg2+ depletion and even under low PIP2 conditions; kinase-domain and pore mutants indicate activation site is distinct from the kinase domain.\",\n      \"method\": \"Aequorin bioluminescence screen, whole-cell patch-clamp, TRPM7 domain mutant analysis\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — screening plus mutagenesis localizing agonist binding site\",\n      \"pmids\": [\"24633576\"],\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; blocking TRPM7 channel conductance reduces Ca2+ influx and accelerates axonal polarization and outgrowth, demonstrating that TRPM7-mediated Ca2+ influx inhibits axonal outgrowth via the F-actin/α-actinin-1 complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, shRNA knockdown, waixenicin A pharmacological blockade, Ca2+ imaging\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP combined with functional rescue and Ca2+ imaging\",\n      \"pmids\": [\"25502295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPM7 kinase activity (not channel activity) regulates mast cell degranulation and histamine release; TRPM7 kinase modulates sensitivity to intracellular Ca2+ and extracellular Mg2+ during IgE-dependent exocytosis, and affects granule mobility/contents.\",\n      \"method\": \"Comparison of TRPM7+/ΔK and TRPM7KR (kinase-dead point mutant) mouse mast cells; exocytosis assays, histamine release measurements\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic separation of channel and kinase activities in mouse models with specific functional readout\",\n      \"pmids\": [\"26660477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aldosterone increases TRPM7 plasma membrane expression and current through a mineralocorticoid receptor (MR)-dependent genomic cascade involving SGK1; this upregulation requires a functioning TRPM7 α-kinase domain, as kinase-dead K1648R-TRPM7 is unresponsive to aldosterone.\",\n      \"method\": \"Whole-cell patch-clamp, cell-surface biotinylation, pharmacological blockade of MR (eplerenone) and SGK1 (GSK-650394), kinase-dead mutant expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — electrophysiology combined with surface protein quantification and mutant analysis\",\n      \"pmids\": [\"27466368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The coiled-coil domain of TRPM7 is required for channel regulation by intracellular Mg2+ and Mg·ATP; C-terminal truncation mutants of zebrafish TRPM7 losing the coiled-coil domain show altered Mg-nucleotide sensitivity.\",\n      \"method\": \"C-terminal truncation mutant analysis by whole-cell patch-clamp electrophysiology in heterologous expression system\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain deletion mutagenesis with direct electrophysiological functional readout\",\n      \"pmids\": [\"27628598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPM7 kinase activity (not channel activity itself) regulates store-operated calcium entry (SOCE)/CRAC currents in B lymphocytes; TRPM7 channel activity is required to maintain endoplasmic reticulum Ca2+ store levels at rest and for refilling after Ca2+ signaling events.\",\n      \"method\": \"TRPM7-/- DT40 B cells, kinase-deficient TRPM7 mutants, pharmacological blockade (NS8593, waixenicin A), Ca2+ imaging, patch-clamp of ICRAC\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological separation of channel/kinase roles with electrophysiology and Ca2+ imaging\",\n      \"pmids\": [\"28130783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A point mutation in the TRPM7 kinase domain deleting kinase activity in mice causes impaired PIP2 metabolism and reduced Ca2+ mobilization in platelets in response to GPVI, CLEC-2, and PAR receptors; altered Syk and phospholipase Cγ2/β3 phosphorylation accounts for the defect; TRPM7 kinase-dead mice are protected from arterial thrombosis and ischemic stroke.\",\n      \"method\": \"Kinase-dead knock-in mice (Trpm7R/R), platelet activation assays, phosphoproteomics, in vivo thrombosis and stroke models\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model with defined signaling mechanism and in vivo disease phenotype\",\n      \"pmids\": [\"29146750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPM7 kinase domain is essential for normal synapse density; re-expression of the α-kinase domain alone (without channel) rescues synapse density, plasticity, and memory in TRPM7 conditional knockout mice, likely through kinase-mediated phosphorylation of cofilin.\",\n      \"method\": \"Hippocampal-specific TRPM7 knockdown/conditional KO in mice, electrophysiology (LTP), behavioral tests, rescue with α-kinase domain construct, cofilin phosphorylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific rescue in vivo with multiple functional readouts\",\n      \"pmids\": [\"29924992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPM7 kinase activity in ameloblasts phosphorylates CREB directly (shown by co-immunoprecipitation); kinase-inactive knock-in mice exhibit defective ameloblast differentiation with impaired phosphorylation of Smad1/5/9, p38, and CREB at the pre-secretory stage, demonstrating kinase-dependent control of tooth enamel formation.\",\n      \"method\": \"TRPM7 kinase-dead (KR) knock-in mice, immunoprecipitation of CREB-TRPM7 complex, phosphoprotein analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model + co-IP identifying CREB as direct kinase substrate\",\n      \"pmids\": [\"29273814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPM7 channel and kinase both contribute to antigen gathering and BCR signaling in B cells; TRPM7-deficient or kinase-deficient DT40 B cells show defective antigen gathering, prolonged BCR signaling, and altered lipid metabolism; blocking TRPM7 function impairs antigen internalization and presentation to T cells.\",\n      \"method\": \"TRPM7-/- and kinase-dead B cell lines, BCR signaling assays, antigen internalization and presentation assays, lipid metabolism analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic separation of channel and kinase functions with functional cellular readout\",\n      \"pmids\": [\"29871912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPM7 ion channel activity (not kinase activity) is required for B cell development; mice lacking TRPM7 in B cells exhibit developmental block at the pro-B cell stage; high extracellular Mg2+ partially rescues TRPM7-deficient B cell development in vitro.\",\n      \"method\": \"B cell-specific TRPM7 knockout mice, flow cytometry of B cell developmental stages, Mg2+ rescue experiments in vitro\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO mouse with defined developmental block and Mg2+ rescue\",\n      \"pmids\": [\"29871911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPM7 signaling regulates RhoA activity and actin polymerization, MRTF-A–Filamin A complex formation, and MRTF-A/SRF-dependent gene expression through Mg2+ influx via the channel and phosphorylation of RhoA by TRPM7 kinase.\",\n      \"method\": \"TRPM7 pharmacological inhibition (NS8593), CRISPR knockout, RhoA activity assays, actin polymerization assays, co-immunoprecipitation of MRTF-A/Filamin A\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological tools combined with biochemical pathway dissection\",\n      \"pmids\": [\"31844251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Native TRPM7 channels in rodent brain form high-molecular-weight multi-protein complexes containing CNNM1-4 metal transporter proteins and the small GTPase ARL15; reconstitution experiments confirm TRPM7/CNNM/ARL15 ternary complex formation, which specifically impacts TRPM7 channel activity.\",\n      \"method\": \"Multi-epitope affinity purification from native brain tissue, quantitative mass spectrometry, heterologous reconstitution, patch-clamp electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — native complex purification from brain + MS + reconstitution + electrophysiology\",\n      \"pmids\": [\"34766907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CNNM proteins selectively bind to and stimulate TRPM7 channel-mediated divalent cation entry; CNNMs require the TRPM7 channel pore for divalent uptake; PRL phosphatases stimulate TRPM7-dependent divalent entry via CNNMs; CNNMs also possess separate TRPM7-independent Mg2+ efflux activity.\",\n      \"method\": \"CNNM knockouts in HEK-293 cells, pore-dead TRPM7 mutants, whole-cell patch-clamp, divalent cation uptake assays, co-expression studies\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO cells, pore mutants, electrophysiology, and functional divalent uptake assays\",\n      \"pmids\": [\"34928937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPM7 kinase cleaved fragments (M7CKs) accumulate in macrophage nuclei upon Mg2+ stimulation and phosphorylate Histone H3 at serine 10 at promoters of inflammatory cytokines, creating a pro-osteogenic immune microenvironment.\",\n      \"method\": \"Nuclear fractionation, ChIP, TRPM7-dependent H3S10 phosphorylation assays, macrophage Mg2+ influx measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and nuclear fractionation demonstrating kinase-dependent histone modification in primary immune cells\",\n      \"pmids\": [\"34001887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPM7 kinase activity regulates neutrophil transmigration along CXCL8 gradient and ROS production in response to LPS; TRPM7 kinase affects Akt1/mTOR signaling in neutrophils, controlling transmigration and effector function.\",\n      \"method\": \"Pharmacological TRPM7 channel and kinase inhibitors, murine neutrophils with genetic kinase ablation, transwell migration assay, ROS production assay, Akt/mTOR signaling analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic kinase ablation confirmed by pharmacology with defined signaling pathway\",\n      \"pmids\": [\"33658993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intracellular Mg2+ binds to a conserved N1097 inter-subunit site in the lower channel gate of TRPM7, stabilizing the closed state; removal of Mg2+ from this site favors channel opening, establishing the structural mechanism of Mg2+-dependent TRPM7 inhibition.\",\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 — mutagenesis at identified gate residue with single-channel electrophysiology and MD simulation validation\",\n      \"pmids\": [\"35389104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPM7 is required for phagosome maturation during efferocytosis in macrophages; TRPM7 mediates a pH-activated cationic current that sustains phagosomal acidification; TRPM7-dependent peri-phagosomal Ca2+ signals are necessary for phagosome maturation.\",\n      \"method\": \"siRNA screen, perforated patch electrophysiology, genetically-encoded Ca2+ sensor in mice, phagosome acidification and cargo digestion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA screen hit validated by in vivo Ca2+ sensor and direct electrophysiology of phagosomal current\",\n      \"pmids\": [\"35680919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TrpM7 is palmitoylated at a cysteine cluster at the C-terminal end of its Trp domain by zDHHC17 (Golgi) and zDHHC5 (surface membrane); palmitoylation controls TrpM7 exit from the ER and distribution between cell surface and intracellular vesicles; non-palmitoylated TrpM7 is sequestered intracellularly and shows significantly reduced transmembrane Ca2+ uptake.\",\n      \"method\": \"RUSH trafficking system, palmitoylation site mutagenesis, zDHHC knockdown/identification, Ca2+ uptake assay\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct identification of palmitoyl-transferases, trafficking assay, and functional Ca2+ transport measurement\",\n      \"pmids\": [\"36027648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A TRPM7 gain-of-function mutation (A931T) in transmembrane domain S3 generates an omega current carried by Na+ that is insensitive to the pore blocker Gd3+; expression of A931T in trigeminal ganglion neurons lowers current threshold, resting membrane potential, and increases evoked firing, suggesting this mutation underlies pain in familial trigeminal neuralgia.\",\n      \"method\": \"Whole-exome sequencing, patch-clamp analysis of mutant channels, Na+/Ca2+ imaging, transfection of TG neurons with A931T\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — electrophysiological characterization in HEK and native neurons with mutagenesis identifying mechanism\",\n      \"pmids\": [\"36095216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of TRPM7 reveal two distinct activation mechanisms: gain-of-function mutation and the agonist naltriben show different conformational dynamics and domain involvement; a binding site for potent selective inhibitors was identified in the closed state; inhibitors act by stabilizing the TRPM7 closed state.\",\n      \"method\": \"Cryo-EM structure determination, functional mutagenesis, molecular dynamics simulations, electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with mutagenesis and MD simulations providing atomic-level mechanism\",\n      \"pmids\": [\"37156763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRPM7 channel transcriptionally regulates glycolytic enzyme SLC2A3/GLUT3 via Ca2+ influx-induced calcineurin activation, acting through CRTC2 and CREB as downstream effectors; TRPM7 deletion suppresses cancer cell glycolysis and xenograft tumor growth, and inhibits postnatal retinal angiogenesis.\",\n      \"method\": \"RNA-seq, metabolomics, TRPM7 knockout cells and mice, calcineurin inhibition, CRTC2/CREB rescue experiments, in vivo tumor and retinal angiogenesis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics plus genetic rescue experiments defining complete signaling axis\",\n      \"pmids\": [\"36878949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRL-1/2 phosphatases enhance TRPM7 Mg2+ channel activity by preventing CNNM3 interaction with TRPM7; ARL15 (small GTPase) increases CNNM3/TRPM7 complex formation to reduce TRPM7 activity; at low cellular Mg2+, CNNM3-TRPM7 interaction is reduced in a PRL-dependent manner, coupling Mg2+ sensing to TRPM7 function.\",\n      \"method\": \"Genetically-encoded intracellular Mg2+ reporter, co-immunoprecipitation, TRPM7 activity assays, PRL-1/2 KO cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel Mg2+ reporter plus co-IP and genetic KO establishing regulatory complex dynamics\",\n      \"pmids\": [\"36972446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPM6 kinase cross-phosphorylates TRPM7 on serine residues (but not vice versa), alters TRPM7 intracellular trafficking, and inhibits TRPM7-dependent cell growth under hypomagnesic conditions in a kinase-activity-dependent manner.\",\n      \"method\": \"Kinase phosphorylation assays, TRPM7 trafficking analysis in HEK-293 and DT40 cells, kinase-dead TRPM6 mutant complementation, cell growth assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct kinase substrate identification combined with trafficking and growth assays using kinase-dead mutants\",\n      \"pmids\": [\"24858416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPM7 channel stimulation by clozapine or naltriben mediates Zn2+ release from intracellular Zn2+-accumulating vesicles (where TRPM7 localizes) into the cytosol; this Zn2+ release disrupts autophagosome-lysosome fusion by interfering with Sxt17-VAMP8 interaction, arresting autophagy.\",\n      \"method\": \"Zn2+ imaging, TRPM7 pharmacological activation, co-immunoprecipitation of Sxt17-VAMP8, autophagy flux assays, intracellular TRPM7 localization\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanism defined by imaging and co-IP but in single study with pharmacological tools\",\n      \"pmids\": [\"34752845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPM7 kinase deficiency (TRPM7+/Δkinase mice) causes cardiac hypertrophy, fibrosis, and inflammation; reduced cardiac Mg2+ (not Ca2+), upregulation of calpain, and increased pro-fibrotic cytokine signaling (SMAD3, TGFβ) are downstream consequences; TRPM7+/Δkinase macrophages drive cardiac fibroblast activation.\",\n      \"method\": \"TRPM7 kinase-deficient mice, cardiac histology, cytokine profiling, macrophage-fibroblast co-culture, intracellular ion measurements, intra-vital microscopy\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined mouse genetic model with multiple mechanistic readouts including ion measurements and co-culture\",\n      \"pmids\": [\"31250885\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPM7 is a ubiquitous plasma membrane 'chanzyme' consisting of a Mg2+- and Ca2+-permeable divalent cation channel (also conducting Zn2+, Mn2+, and monovalent ions) whose activity is constitutively suppressed by intracellular Mg2+ binding to a conserved lower-gate site (N1097) and by Mg·ATP/Mg·GTP; palmitoylation at its Trp domain controls trafficking between the cell surface and intracellular vesicles; the channel is flanked by a C-terminal α-kinase that is proteolytically released, translocates to the nucleus, and phosphorylates histones (H3S10) to regulate gene expression, while also phosphorylating cytoplasmic substrates including annexin 1, myosin IIA heavy chain, cofilin, RhoA, and CREB to control actomyosin contractility, cell adhesion, migration, and synaptic density; TRPM7 function is additionally regulated by its assembly into native complexes with CNNM1-4 metal transporters and ARL15, which modulate channel activity; collectively the channel and kinase activities regulate cellular Mg2+/Ca2+/Zn2+ homeostasis, store-operated Ca2+ entry, B cell development, mast cell degranulation, neutrophil transmigration, macrophage efferocytosis, and platelet activation, while loss of TRPM7 expression or activity causes cell death under Mg2+-deplete conditions and mediates ischemic neuronal death in vivo.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRPM7 is a ubiquitously expressed bifunctional 'chanzyme' that couples a divalent cation-permeable channel (Ca²⁺, Mg²⁺, Zn²⁺) to a C-terminal α-kinase domain, integrating ion transport with phosphorylation-dependent signaling to control cell viability, migration, immune cell function, and gene expression. The channel is constitutively suppressed by intracellular Mg²⁺ binding at a conserved lower-gate residue (N1097) and by Mg·ATP, requires PIP2, and is regulated by assembly into native complexes with CNNM1–4 metal transporters and the small GTPase ARL15, which tune divalent cation entry; palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls surface trafficking [PMID:35389104, PMID:34766907, PMID:36027648, PMID:11385574]. The α-kinase domain undergoes proteolytic cleavage, and the released fragment translocates to the nucleus where it phosphorylates histone H3 at Ser10 at target-gene promoters in association with Polycomb complexes, while cytoplasmic substrates including myosin IIA heavy chain, annexin 1, cofilin, RhoA, and CREB control actomyosin contractility, cell migration, synapse density, mast cell degranulation, platelet activation, and neutrophil transmigration [PMID:24855944, PMID:16407977, PMID:29924992, PMID:26660477, PMID:29146750]. A gain-of-function A931T mutation generating a gating-pore omega current in TRPM7 causes familial trigeminal neuralgia, and cryo-EM structures have delineated distinct activation mechanisms by agonists versus gain-of-function mutations and identified a selective-inhibitor binding pocket in the closed state [PMID:36095216, PMID:37156763].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that TRPM7 constitutes a novel class of Mg·ATP-regulated divalent cation channel essential for cell viability resolved the molecular identity of the ubiquitous Mg²⁺-inhibited current and demonstrated that channel loss is cell-lethal.\",\n      \"evidence\": \"Heterologous expression with patch-clamp in HEK-293 and targeted gene deletion in DT40 B cells\",\n      \"pmids\": [\"11385574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Mg·ATP inhibition unresolved\", \"Channel vs. kinase contribution to lethality not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of annexin 1 and subsequently myosin IIA heavy chain as direct TRPM7 kinase substrates established that the kinase domain has autonomous signaling functions beyond ion conduction, linking it to Ca²⁺-dependent membrane dynamics and actomyosin contractility.\",\n      \"evidence\": \"In vitro kinase assays with site-directed mutagenesis (annexin 1 Ser5); co-IP plus kinase-dead mutant analysis and live-cell imaging for myosin IIA\",\n      \"pmids\": [\"15485879\", \"16407977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full kinase substrate repertoire unknown\", \"In vivo relevance of annexin 1 phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that TRPM6 and TRPM7 form distinct homomeric and heteromeric channels with different permeation and pharmacological profiles clarified their non-redundant physiological roles in divalent cation homeostasis.\",\n      \"evidence\": \"Whole-cell and single-channel patch-clamp of homo- and heteromeric channels with pharmacological profiling (2-APB)\",\n      \"pmids\": [\"16636202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly rules of heteromeric channels not determined\", \"Tissue-specific ratio of homo- vs. heteromeric channels unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showing that hippocampal TRPM7 knockdown prevents delayed neuronal death after global ischemia without affecting basal synaptic function established TRPM7 as a mediator of ischemic neuronal injury in vivo.\",\n      \"evidence\": \"Viral shRNA delivery to rat CA1 neurons, electrophysiology (LTP), behavioral testing, histology\",\n      \"pmids\": [\"19734892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream death pathway (Ca²⁺ vs. Zn²⁺ overload) not delineated\", \"Kinase vs. channel contribution to ischemic death not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Rescue of TRPM7-knockdown migration defects by the Mg²⁺ transporter SLC41A2 identified Mg²⁺ as the critical effector ion through which TRPM7 controls Rac/Cdc42 activation and polarized cell migration, separating Mg²⁺-dependent from Ca²⁺-dependent channel functions.\",\n      \"evidence\": \"siRNA knockdown with GTPase activation pulldowns, rescue with kinase-dead TRPM7 and SLC41A2 overexpression, wound-healing assays\",\n      \"pmids\": [\"21208190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Mg²⁺-sensing mechanism linking Rac/Cdc42 activation not identified\", \"In vivo validation in migratory cell types lacking\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that the TRPM7 kinase domain is proteolytically cleaved, translocates to the nucleus, and phosphorylates histone H3 at Ser10 at target promoters revealed an unanticipated mechanism by which an ion channel directly regulates chromatin and gene expression.\",\n      \"evidence\": \"Biochemical fractionation, co-IP with Polycomb proteins, mass spectrometry, in vitro histone kinase assay, Zn²⁺ imaging, transcriptomics\",\n      \"pmids\": [\"24855944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for cleavage not identified\", \"Genome-wide map of H3S10ph targets incomplete\", \"Regulation of cleavage kinetics unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"TRPM6 kinase was found to cross-phosphorylate TRPM7 (but not vice versa), altering TRPM7 trafficking and growth under hypomagnesemia, establishing a directional kinase crosstalk between the two chanzymes.\",\n      \"evidence\": \"Kinase assays, trafficking analysis, kinase-dead TRPM6 complementation in HEK-293 and DT40 cells\",\n      \"pmids\": [\"24858416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites on TRPM7 not mapped\", \"Physiological relevance in epithelial Mg²⁺ transport not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic separation of kinase and channel functions in mouse mast cells showed that kinase activity (not channel conductance) controls IgE-dependent degranulation and histamine release by modulating sensitivity to intracellular Ca²⁺ and extracellular Mg²⁺.\",\n      \"evidence\": \"Comparison of TRPM7+/ΔK and kinase-dead (KR) mouse mast cells, exocytosis and histamine release assays\",\n      \"pmids\": [\"26660477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrate in mast cell exocytic machinery not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In vivo studies using kinase-dead knock-in mice revealed that TRPM7 kinase controls platelet activation via Syk/PLCγ phosphorylation and PIP2 metabolism, protecting against arterial thrombosis and ischemic stroke, and independently maintains synapse density through cofilin phosphorylation.\",\n      \"evidence\": \"Trpm7R/R kinase-dead mice with platelet assays, phosphoproteomics, in vivo thrombosis models; hippocampal conditional KO with α-kinase rescue, LTP, and behavioral tests\",\n      \"pmids\": [\"29146750\", \"29924992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full phosphoproteomic substrate spectrum in platelets and neurons not defined\", \"Whether kinase effects on cofilin are direct or via intermediate kinases unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"B cell-specific TRPM7 knockout revealed that channel-mediated Mg²⁺ influx is essential for B cell development at the pro-B stage, while both channel and kinase contribute to BCR signaling, antigen gathering, and presentation to T cells.\",\n      \"evidence\": \"B cell-specific KO mice, flow cytometry of developmental stages, Mg²⁺ rescue, kinase-dead B cell lines with BCR signaling and antigen presentation assays\",\n      \"pmids\": [\"29871911\", \"29871912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Mg²⁺ influx specifically permits pro-B to pre-B transition is mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TRPM7 was shown to control the RhoA–actin–MRTF-A/SRF transcriptional axis through both Mg²⁺ influx and direct RhoA phosphorylation by the kinase, connecting channel activity to gene expression programs governing cytoskeletal remodeling.\",\n      \"evidence\": \"CRISPR KO, pharmacological inhibition (NS8593), RhoA activity assays, co-IP of MRTF-A/Filamin A\",\n      \"pmids\": [\"31844251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RhoA phosphorylation site by TRPM7 kinase not mapped\", \"Relative contribution of Mg²⁺ vs. kinase in different cell types unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Purification of native TRPM7 complexes from brain identified CNNM1–4 and ARL15 as stable partners that modulate channel activity, and subsequent studies showed PRL phosphatases tune this complex to couple cellular Mg²⁺ sensing to TRPM7 function.\",\n      \"evidence\": \"Multi-epitope affinity purification, quantitative mass spectrometry, reconstitution with patch-clamp; genetically encoded Mg²⁺ reporter, PRL-1/2 KO cells, co-IP\",\n      \"pmids\": [\"34766907\", \"34928937\", \"36972446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CNNM–TRPM7 interface unknown\", \"Whether CNNM regulation of TRPM7 operates identically in all tissues not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of N1097 as the intracellular Mg²⁺-binding site in the lower channel gate provided the first structural explanation for how physiological Mg²⁺ suppresses TRPM7 opening.\",\n      \"evidence\": \"Site-directed mutagenesis, single-channel electrophysiology, molecular dynamics simulations\",\n      \"pmids\": [\"35389104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length high-resolution structure with Mg²⁺ at this site not yet available\", \"Cooperativity among four subunit gate sites not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that TRPM7 localizes to phagosomes, conducts a pH-activated cationic current, and sustains phagosomal acidification established a previously unknown role for TRPM7 in macrophage efferocytosis.\",\n      \"evidence\": \"siRNA screen, perforated patch electrophysiology, genetically encoded phagosomal Ca²⁺ sensor in mice, cargo digestion assays\",\n      \"pmids\": [\"35680919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the pH sensor within TRPM7 not determined\", \"Whether phagosomal TRPM7 is palmitoylation-dependent not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that palmitoylation at the TRP domain by zDHHC17/zDHHC5 controls TRPM7 ER exit and surface residence revealed a post-translational trafficking switch regulating channel availability.\",\n      \"evidence\": \"RUSH trafficking system, palmitoylation-site mutagenesis, zDHHC knockdown, Ca²⁺ uptake assays\",\n      \"pmids\": [\"36027648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic regulation of palmitoylation/depalmitoylation cycle not characterized\", \"Which thioesterase depalmitoylates TRPM7 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A TRPM7 gain-of-function mutation (A931T) was linked to familial trigeminal neuralgia by generating a gating-pore omega current that lowers neuronal firing threshold, providing the first Mendelian disease association for TRPM7.\",\n      \"evidence\": \"Whole-exome sequencing, patch-clamp of mutant channels in HEK-293 and trigeminal ganglion neurons, Na⁺/Ca²⁺ imaging\",\n      \"pmids\": [\"36095216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and prevalence in other trigeminal neuralgia cohorts not established\", \"Therapeutic targetability of the omega current not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures of TRPM7 in closed, agonist-bound, and gain-of-function states delineated two distinct activation mechanisms and identified a selective-inhibitor binding pocket, providing an atomic framework for drug design.\",\n      \"evidence\": \"Cryo-EM, functional mutagenesis, molecular dynamics simulations, electrophysiology\",\n      \"pmids\": [\"37156763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of TRPM7 in complex with CNNM/ARL15 not resolved\", \"Kinase-domain conformation relative to channel in full-length structure not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the protease that cleaves the kinase domain, the full substrate repertoire of the kinase in different tissues, the structural basis of the TRPM7–CNNM–ARL15 regulatory complex, and whether channel and kinase activities can be therapeutically targeted independently.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease identity for kinase cleavage unknown\", \"Tissue-specific kinase substrate mapping incomplete\", \"No TRPM7–CNNM–ARL15 co-structure available\", \"Selective kinase-only or channel-only inhibitors not yet validated in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 8, 12, 16, 17, 18, 21, 24, 25]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 8, 17, 18, 33]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 3, 15, 22, 23, 26, 27]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 13, 28]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 24]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [28, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 13, 16, 21, 25, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 19, 20, 25, 27]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 6, 22, 23, 26]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 21, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\n      \"TRPM7-CNNM-ARL15\",\n      \"TRPM6/TRPM7 heteromer\"\n    ],\n    \"partners\": [\n      \"CNNM1\",\n      \"CNNM3\",\n      \"ARL15\",\n      \"TRPM6\",\n      \"ACTN1\",\n      \"MYH9\",\n      \"ANXA1\",\n      \"ZDHHC17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}