Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a unique ion channel-kinase fusion protein that functions as a calcium- and magnesium-permeable cation channel with an intrinsic serine/threonine protein kinase domain. Essential for cellular ion homeostasis, TRPM7 regulates Mg2+ and Ca2+ influx and is required for multiple developmental processes including melanophore survival, mechanosensory neuron function, dopaminergic neuron development, cardiac pacemaking, exocrine pancreas development, and skeletal mineralization. The protein localizes primarily to the plasma membrane where it forms homo-tetrameric channel complexes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation based on phylogenetic evidence. The deep research confirms TRPM7 contains a C-terminal alpha-kinase domain with serine/threonine kinase activity. However, this term is too general - the specific kinase type should be specified. Reason: While TRPM7 does have protein kinase activity, the more specific term GO:0004674 (protein serine/threonine kinase activity) better represents the actual molecular function of the alpha-kinase domain. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002674401 Β· TRPM channel-kinase ancestral node SUPPORTS TRANSFER Transfer is sound but 'protein kinase activity' is too generic; TRPM7's C-terminal alpha-kinase is a serine/threonine kinase (GO:0004674). UniProtKB:Q96QT4 Β· human TRPM7 SUPPORTS TRANSFER Ortholog's alpha-kinase domain has serine/threonine kinase activity, supporting the more specific replacement term. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md The C-terminal Ξ±-kinase domain of Trpm7 can phosphorylate itself and other substrates, though its in vivo targets are still being characterized. |
| GO:0005262 calcium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation well-supported by experimental evidence. TRPM7 forms a calcium-permeable cation channel, though Ca2+ is actually one of the least permeable divalent cations compared to Mg2+, Co2+, and others. Reason: The deep research confirms TRPM7 functions as a calcium channel, mediating Ca2+ influx across membranes. This is a core molecular function. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md Trpm7 forms a ion channel that mediates Ca^2+ influx PMID:27628598 TRPM7 exhibits an outwardly rectifying current-voltage relationship due to voltage-dependent block by Mg2+ and calcium (Ca2+) at negative voltages file:DANRE/trpm7/trpm7-deep-research-falcon.md TRPM7 forms a plasma-membrane cation channel permeable to **Mg2+**, **Ca2+**, and **Zn2+**, with broader permeability to other divalent cations |
| GO:0006816 calcium ion transport | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation correctly identifies TRPM7's role in calcium transport. The channel conducts Ca2+ ions across membranes as part of its divalent cation transport function. Reason: TRPM7 mediates calcium ion transport across the plasma membrane. The row is retained as a true parent; the core claim is carried by its specific descendant calcium ion transmembrane transport (GO:0070588) under the calcium-channel core function, though the channel also transports other divalent cations. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md As an ion channel, TRPM7 mediates the influx of divalent cations (notably Ca^2+ and Mg^2+) across cell membranes, which is crucial for maintaining cellular ion homeostasis |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation strongly supported by experimental evidence. TRPM7 is an integral membrane protein that primarily localizes to the plasma membrane. Reason: Multiple lines of evidence confirm TRPM7 localizes to the plasma membrane where it functions as a transmembrane ion channel. This is a core cellular component. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md Trpm7 is an **integral membrane protein** that primarily localizes to the **plasma membrane** of cells |
| GO:0098655 monoatomic cation transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation correctly identifies TRPM7's broad cation transport function. The channel conducts various monoatomic cations including Ca2+, Mg2+, Zn2+, Ni2+, and others. Reason: TRPM7 functions as a non-selective cation channel that transports multiple monoatomic cations across membranes. The row is retained as a true parent; the core claim is carried by its specific descendant calcium ion transmembrane transport (GO:0070588). Supporting Evidence: PMID:27628598 Mouse TRPM7 (mTRPM7) has been shown to best permeate zinc (Zn2+) and nickel (Ni2+), followed by barium (Ba2+), cobalt (Co2+), magnesium (Mg2+), manganese (Mn2+), strontium (Sr2+), cadmium (Cd2+) and calcium (Ca2+) |
| GO:0004672 protein kinase activity | IEA GO_REF:0000117 | MODIFY | Summary: ARBA-derived IEA for generic protein kinase activity (GO:0004672). The term is correct at the parent level but the C-terminal alpha-kinase domain of TRPM7 is a serine/threonine kinase, so the child term is the informative one. Reason: TRPM7 is a channel-kinase whose C-terminal alpha-kinase domain phosphorylates serine/threonine residues (PMID:27628598 describes the protein as an ion channel fused to an alpha-kinase); the generic protein kinase term should be replaced by protein serine/threonine kinase activity (GO:0004674), which GOA already carries for this gene and which core_functions lists as the kinase activity. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md Alpha-kinases are atypical serine/threonine kinases that phosphorylate substrates within alpha-helical regions |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation correctly identifies the specific kinase type. The alpha-kinase domain of TRPM7 has serine/threonine kinase activity. Reason: TRPM7 contains an alpha-kinase domain that phosphorylates serine/threonine residues. This is a core molecular function. Falcon deep research confirms the catalyzed reaction (phosphotransfer to Ser/Thr plus autophosphorylation), consistent with the UniProt EC 2.7.11.1 catalytic activity and the C-terminal alpha-kinase domain (residues 1503-1733). Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md the C-terminal Ξ±-kinase of Trpm7 phosphorylates serine/threonine residues on target proteins file:DANRE/trpm7/trpm7-deep-research-falcon.md Ξ±-kinase domain transfers phosphate from ATP to **serine/threonine residues** on protein substrates and on TRPM7 itself (autophosphorylation) |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro. Correct general term for TRPM7's ion channel function. Reason: TRPM7 functions as an ion channel that conducts monoatomic cations. This is a core molecular function, though more specific terms also apply. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md It functions as a **calcium- and magnesium-permeable cation channel** with an intrinsic **serine/threonine protein kinase** domain file:DANRE/trpm7/trpm7-deep-research-falcon.md Channel opening requires **PIP2**; receptor pathways that deplete PIP2 reduce TRPM7 activity. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | REMOVE | Summary: IEA from the UniProt subcellular-location keyword mapping. The only support for a nuclear location is the statistical ARBA prediction carried in the UniProt record; the nuclear M7CK kinase fragment reported in mammalian cells is not evidence that the full-length channel-kinase annotated here localizes to the nucleus. Reason: The only support for a nuclear location is a statistical ARBA/UniRule-derived prediction carried in the UniProt record (ARBA00004123), with no experimental localization in any species behind it. The cleaved TRPM7 kinase fragment (M7CK) reported to reach the nucleus in mammalian cells is not evidence that the full-length channel-kinase, which is the entity annotated here, localizes there: every direct localization study places the channel in the plasma membrane and intracellular vesicles. The row is removed as an over-propagated electronic inference rather than as a contradicted experimental result. Supporting Evidence: file:DANRE/trpm7/trpm7-uniprot.txt Nucleus {ECO:0000256|ARBA:ARBA00023242} file:DANRE/trpm7/trpm7-deep-research.md Trpm7 is an **integral membrane protein** that primarily localizes to the **plasma membrane** of cells |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from the UniProt subcellular-location keyword (SL-0039, Cell membrane). The same location is independently supported by the IBA row and by direct experimental work on the zebrafish protein (PMID:27628598). Reason: Plasma membrane is where Trpm7 acts as an ion channel, and this is shown directly for the zebrafish protein in PMID:27628598, where HA-tagged Danio rerio TRPM7 expressed in HEK293 T-REx cells was assessed for plasma membrane expression by whole-cell patch clamp and produced the characteristic Mg2+-sensitive currents; the UniProt record carries the matching 'Cell membrane; Multi-pass membrane protein' SUBCELLULAR LOCATION line. The electronic mapping is therefore correct and the location is a core component. Supporting Evidence: PMID:27628598 we assessed all positive clones for plasma membrane expression using the whole-cell patch clamp technique PMID:27628598 HEK293 T-REx cells stably expressing HA-tagged Danio rerio TRPM7 (drTRPM7) file:DANRE/trpm7/trpm7-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000256|ARBA:ARBA00004651}; file:DANRE/trpm7/trpm7-deep-research.md Trpm7 is an **integral membrane protein** that primarily localizes to the **plasma membrane** of cells |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation. Very general term - plasma membrane is more specific. Reason: TRPM7 is a membrane protein, though plasma membrane is more specific. Acceptable general annotation. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md integral membrane protein |
| GO:0030001 metal ion transport | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation correctly identifies metal ion transport function. Reason: TRPM7 transports various metal ions including Ca2+, Mg2+, Zn2+, Ni2+. Core biological process. Supporting Evidence: PMID:27628598 best permeate zinc (Zn2+) and nickel (Ni2+), followed by barium (Ba2+), cobalt (Co2+), magnesium (Mg2+), manganese (Mn2+) |
| GO:0051262 protein tetramerization | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro. TRPM7 contains a coiled-coil tetramerization domain and forms homo-tetrameric complexes. Reason: TRPM7 forms tetrameric channel complexes via its coiled-coil domain. This is essential for channel assembly and function. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md This coiled-coil helps four Trpm7 subunits come together to form a functional channel complex |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro. General term for transmembrane transport activity. Reason: TRPM7 mediates transmembrane transport of ions. Core function though more specific terms also apply. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md spans the membrane (with six transmembrane helices per subunit) and forms homo-tetrameric channel complexes in the lipid bilayer |
| GO:0001966 thigmotaxis | IMP PMID:38970357 Zebrafish trpm7 mutants show reduced motility in free moveme... | KEEP AS NON CORE | Summary: thigmotaxis (GO:0001966) IMP: zebrafish trpm7 mutants show reduced motility/movement (abstract-only, PMID:38970357). A downstream behavioral phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:38970357 compromised motility with their movement distance shorter than wild-type larvae |
| GO:0036269 swimming behavior | IMP PMID:38970357 Zebrafish trpm7 mutants show reduced motility in free moveme... | KEEP AS NON CORE | Summary: swimming behavior (GO:0036269) IMP: trpm7 mutants show compromised motility and reduced movement distance (PMID:38970357). Downstream behavioral phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:38970357 compromised motility with their movement distance shorter than wild-type larvae |
| GO:0005886 plasma membrane | IDA PMID:27628598 The coiled-coil domain of zebrafish TRPM7 regulates MgΒ·nucle... | ACCEPT | Summary: IDA evidence from electrophysiology studies confirming plasma membrane localization of TRPM7. Reason: The ZFIN IDA rests on whole-cell patch-clamp recordings of HA-tagged zebrafish Trpm7 expressed in HEK293 T-REx cells, where the clones were selected for plasma-membrane expression and gave the characteristic outwardly rectifying divalent-cation current; a channel that carries a measurable whole-cell current is by definition at the plasma membrane, and the same paper's Mg2+ homeostasis readout depends on that surface conductance. The IBA and IEA rows for the same term are argued on the same evidence, so the location is accepted as the core cellular component. Supporting Evidence: PMID:27628598 Patch-clamp experiments were performed in the tight-seal whole-cell configuration... HEK293 T-REx cells stably expressing HA-tagged Danio rerio TRPM7 (drTRPM7) file:DANRE/trpm7/trpm7-deep-research.md Trpm7 is an **integral membrane protein** that primarily localizes to the **plasma membrane** of cells file:DANRE/trpm7/trpm7-deep-research-falcon.md TRPM7 localizes to the **plasma membrane** and also to intracellular pools described as **tubulovesicular/synaptic vesicle-like compartments**. |
| GO:0010960 magnesium ion homeostasis | IDA PMID:27628598 The coiled-coil domain of zebrafish TRPM7 regulates MgΒ·nucle... | ACCEPT | Summary: IDA evidence from electrophysiology showing TRPM7 regulates Mg2+ homeostasis and is regulated by intracellular Mg2+. Reason: Direct experimental evidence shows TRPM7 is essential for magnesium homeostasis. This is a core function. Supporting Evidence: PMID:27628598 the channel's regulation by magnesium (Mg) and MgΒ·adenosine triphosphate (MgΒ·ATP)... A dose-response curve fit to averaged currents extracted at 200 s into the experiment revealed a half-maximal inhibitory concentration (IC50) of 778 Β± 291 ΞΌM PMID:27628598 Based on this profile and the effects of divalent substitution/complementation experiments, the TRPM7 channel function is thought to serve as a primary mechanism for cellular Mg2+ homeostasis file:DANRE/trpm7/trpm7-deep-research-falcon.md reduced whole-embryo **total magnesium** and **total calcium** by early larval stages, consistent with TRPM7 acting as an in vivo regulator of organismal divalent-cation balance |
| GO:0030001 metal ion transport | IDA PMID:27628598 The coiled-coil domain of zebrafish TRPM7 regulates MgΒ·nucle... | ACCEPT | Summary: IDA evidence from electrophysiology demonstrating TRPM7 conducts various metal ions including Ca2+, Mg2+, Zn2+, Ni2+. Reason: Direct experimental evidence shows TRPM7 transports multiple metal ions. Core function. Supporting Evidence: PMID:27628598 TRPM7 conducted Ca2+ the least compared to other divalents, with cobalt and magnesium permeating the best PMID:27628598 Mouse TRPM7 (mTRPM7) has been shown to best permeate zinc (Zn2+) and nickel (Ni2+), followed by barium (Ba2+), cobalt (Co2+), magnesium (Mg2+) |
| GO:0048066 developmental pigmentation | IMP PMID:9007256 Zebrafish pigmentation mutations and the processes of neural... | KEEP AS NON CORE | Summary: developmental pigmentation (GO:0048066) IMP: trpm7 mutants show melanophore death/pigmentation defects (PMID:9007256/17290233). Downstream of channel loss. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:17290233 death of melanophores and temporary paralysis |
| GO:0002027 regulation of heart rate | IMP PMID:23878236 Ion channel-kinase TRPM7 is required for maintaining cardiac... | KEEP AS NON CORE | Summary: regulation of heart rate (GO:0002027) IMP: TRPM7 is required for cardiac automaticity; knockdown disrupts pacemaking (PMID:23878236). Downstream physiological phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:23878236 is required for cardiac automaticity in these specialized tissues |
| GO:0003014 renal system process | IMP PMID:20881241 trpm7 regulation of in vivo cation homeostasis and kidney fu... | KEEP AS NON CORE | Summary: renal system process (GO:0003014) IMP: trpm7 mutants develop kidney stones and disturbed cation/phosphate handling (PMID:20881241). Downstream of cation-homeostasis loss. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:20881241 trpm7 mutants develop kidney stones by early larval stages |
| GO:0055080 monoatomic cation homeostasis | IMP PMID:20881241 trpm7 regulation of in vivo cation homeostasis and kidney fu... | ACCEPT | Summary: IMP evidence showing trpm7 regulates systemic Ca2+ and Mg2+ homeostasis, with mutants having dysregulated ion levels. Reason: Experimental evidence demonstrates TRPM7 is essential for maintaining organismal cation homeostasis. The row is retained as a true parent; the core claim is carried by its specific descendant magnesium ion homeostasis (GO:0010960). Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md Zebrafish *trpm7* mutants have dysregulated Ca^2+ and Mg^2+ levels in bodily fluids, leading to **abnormal mineralization** of skeletal tissues PMID:20881241 Sep 29. trpm7 regulation of in vivo cation homeostasis and kidney function involves stanniocalcin 1 and fgf23. file:DANRE/trpm7/trpm7-deep-research-falcon.md In zebrafish, **trpm7 mRNA is broadly expressed**, with particularly high abundance in **kidney tubules** (pronephric/mesonephric) and in the **corpuscles of Stannius** (an endocrine organ involved in ionic homeostasis), supporting a primary role in systemic divalent-cation regulation and renal physiology |
| GO:0007346 regulation of mitotic cell cycle | IMP PMID:21183474 Transient receptor potential ion channel Trpm7 regulates exo... | KEEP AS NON CORE | Summary: IMP evidence suggesting TRPM7 affects cell proliferation in pancreatic development through Mg2+-sensitive signaling. Reason: While TRPM7 affects cell proliferation, this is likely secondary to its primary ion homeostasis function. Not a core function but a downstream effect. Supporting Evidence: PMID:27628598 Based on this profile and the effects of divalent substitution/complementation experiments, the TRPM7 channel function is thought to serve as a primary mechanism for cellular Mg2+ homeostasis and be essential for cell proliferation PMID:21183474 Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer. |
| GO:0031017 exocrine pancreas development | IMP PMID:21183474 Transient receptor potential ion channel Trpm7 regulates exo... | KEEP AS NON CORE | Summary: exocrine pancreas development (GO:0031017) IMP: trpm7 (sweetbread) mutants have hypoplastic acini; Mg2+ supplementation partially rescues (PMID:21183474), showing the defect is downstream of Mg2+ handling. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:21183474 partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving |
| GO:0050678 regulation of epithelial cell proliferation | IMP PMID:21183474 Transient receptor potential ion channel Trpm7 regulates exo... | KEEP AS NON CORE | Summary: IMP evidence from pancreas study showing TRPM7 affects epithelial proliferation. Reason: TRPM7 affects epithelial proliferation through its ion homeostasis function, but this is a downstream effect rather than a core function. Supporting Evidence: file:DANRE/trpm7/trpm7-deep-research.md it may relate to Trpm7βs role in regulating cellular proliferation or differentiation in endodermal tissues PMID:21183474 Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer. |
| GO:0046928 regulation of neurotransmitter secretion | IMP PMID:21832193 TRPM7 is required within zebrafish sensory neurons for the a... | KEEP AS NON CORE | Summary: regulation of neurotransmitter secretion (GO:0046928) IMP: TRPM7 is required in sensory neurons for touch-evoked escape (PMID:21832193). Downstream neuronal phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:21832193 cause the touch-unresponsive zebrafish mutant |
| GO:0006582 melanin metabolic process | IMP PMID:17290233 Cell death of melanophores in zebrafish trpm7 mutant embryos... | KEEP AS NON CORE | Summary: melanin metabolic process (GO:0006582) IMP: melanophore death in trpm7 mutants depends on melanin synthesis (PMID:17290233). Downstream of channel loss. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:17290233 death of melanophores and temporary paralysis |
| GO:0001503 ossification | IMP PMID:15823540 Defective skeletogenesis with kidney stone formation in dwar... | KEEP AS NON CORE | Summary: ossification (GO:0001503) IMP: trpm7 (touchtone/nutria) dwarf mutants have defective skeletogenesis (PMID:15823540). Downstream developmental phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:15823540 severe growth retardation and gross alterations in skeletal |
| GO:0030318 melanocyte differentiation | IMP PMID:15823540 Defective skeletogenesis with kidney stone formation in dwar... | KEEP AS NON CORE | Summary: melanocyte differentiation (GO:0030318) IMP: trpm7 mutants have melanophore/pigment-cell defects (PMID:15823540). Downstream of channel loss. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:15823540 severe growth retardation and gross alterations in skeletal |
| GO:0001501 skeletal system development | IMP PMID:15823540 Defective skeletogenesis with kidney stone formation in dwar... | KEEP AS NON CORE | Summary: skeletal system development (GO:0001501) IMP: trpm7 mutants show gross skeletal alterations and growth retardation (PMID:15823540). Downstream developmental phenotype. Reason: TRPM7's molecular work is divalent-cation (Mg2+/Ca2+) conductance and alpha-kinase activity; this phenotype is a downstream consequence of loss of that function in the affected tissue rather than a process TRPM7 executes. Retained as acts_upstream_of_or_within (non-core). Supporting Evidence: PMID:15823540 severe growth retardation and gross alterations in skeletal |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding (GO:0005524) by the C-terminal alpha-kinase domain of the TRPM7 channel-kinase. Kinase catalysis requires ATP binding. Reason: TRPM7 fuses an ion channel to an alpha-kinase (PMID:27628598); the kinase domain binds ATP for catalysis. Broad IEA correctly captured; core molecular function. Supporting Evidence: PMID:27628598 TRPM7 is a unique fusion protein of an ion channel and an Ξ±-kinase |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | ACCEPT | Summary: monoatomic ion transport (GO:0006811) is the broad transport process for the TRPM7 divalent-cation channel. Correct but general. Reason: TRPM7 conducts divalent cations and regulates in vivo cation homeostasis (PMID:20881241); the broad ion-transport IEA is correct. More specific transport terms (Ca2+/cation) are also present. Supporting Evidence: PMID:20881241 an important regulator of cation homeostasis as well as kidney function in vivo |
| GO:0008324 monoatomic cation transmembrane transporter activity | IEA GO_REF:0000117 | MODIFY | Summary: ARBA-derived IEA placing TRPM7 at the broad monoatomic cation transmembrane transporter level (GO:0008324). The term is true but under-specific: TRPM7 is a Mg2+-permeable channel-kinase, and the zebrafish evidence (Mg2+ homeostasis IDA on PMID:27628598; Mg2+ supplementation rescuing the trpm7 mutant exocrine-pancreas defect, PMID:21183474) supports magnesium ion transmembrane transporter activity (GO:0015095), an is_a descendant of GO:0008324, as the specific activity. Reason: The broad cation-transporter term is not wrong, but the activity the evidence actually supports is Mg2+ conductance. PMID:27628598 (full text) characterizes zebrafish Trpm7 as a divalent-cation channel whose permeation series includes Mg2+ and whose channel function is the primary mechanism of cellular Mg2+ homeostasis, and the same paper grounds the GO:0010960 IDA row. PMID:21183474 shows that dietary Mg2+ partially rescues the exocrine-pancreas defect of trpm7 mutants, which is the in vivo readout expected for loss of a Mg2+ entry channel. GO:0015095 (verified in QuickGO as an is_a descendant of GO:0008324) therefore replaces the parent; the calcium channel activity row remains for the Ca2+ component. This is the core molecular function listed in core_functions. Proposed replacements: magnesium ion transmembrane transporter activity Supporting Evidence: PMID:27628598 Mouse TRPM7 (mTRPM7) has been shown to best permeate zinc (Zn2+) and nickel (Ni2+), followed by barium (Ba2+), cobalt (Co2+), magnesium (Mg2+), manganese (Mn2+), strontium (Sr2+), cadmium (Cd2+) and calcium (Ca2+) PMID:27628598 the TRPM7 channel function is thought to serve as a primary mechanism for cellular Mg2+ homeostasis PMID:21183474 Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000108 | ACCEPT | Summary: calcium ion transmembrane transport (GO:0070588) is the specific transport process for Ca2+ conducted by TRPM7. trpm7 mutants show reduced total calcium in vivo. Reason: TRPM7 conducts Ca2+ across membranes; zebrafish trpm7 mutants have reduced total calcium and disturbed calcium homeostasis (PMID:20881241). Core biological process. Supporting Evidence: PMID:20881241 an important regulator of cation homeostasis as well as kidney function in vivo |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How does TRPM7 integrate mechanosensing with magnesium homeostasis in zebrafish development?
Q: What determines the tissue-specific requirements for TRPM7 kinase versus channel activity?
Q: How does TRPM7 regulate cell migration and morphogenesis during gastrulation and organogenesis?
Q: What role does TRPM7 play in left-right asymmetry establishment in the zebrafish embryo?
Experiment: Generate separation-of-function trpm7 alleles (channel-dead pore mutant vs. kinase-dead alpha-kinase mutant) and assay rescue of melanophore survival, total Mg2+/Ca2+ levels, and kidney stone formation in trpm7 mutants.
Hypothesis: TRPM7 channel conductance, but not its kinase activity, is the primary determinant of melanophore survival and cation homeostasis in zebrafish.
Type: CRISPR knock-in / structure-function rescue
Experiment: Measure hcn4 transcript levels and the pacemaker current If in sinoatrial pacemaker cells of trpm7 mutant versus wild-type zebrafish, and test whether hcn4 overexpression rescues bradycardia.
Hypothesis: TRPM7 maintains cardiac automaticity in zebrafish by transcriptionally sustaining hcn4 expression in pacemaker cells, as shown in mouse SAN.
Type: qPCR / electrophysiology
Experiment: Express wild-type and C-terminal coiled-coil truncation drTRPM7 constructs in heterologous cells and patch-clamp the currents across a range of intracellular Mg2+ and Mg-ATP concentrations to map dose-response inhibition.
Hypothesis: The coiled-coil domain confers Mg/Mg-ATP sensitivity that tunes TRPM7 channel activity in a tissue-specific manner relevant to magnesium homeostasis.
Type: whole-cell patch-clamp electrophysiology
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)π View Pathway Visualization Interactive pathway diagram with detailed annotations