Gene Ontology annotation through association of InterPro records with GO terms.

Annotation inferences using phylogenetic trees

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:15823540

Defective skeletogenesis with kidney stone formation in dwarf zebrafish mutant for trpm7.

Zebrafish touchtone/nutria mutants, caused by mutations in trpm7, show severe growth retardation and skeletal defects including altered ossification, in addition to melanophore and touch-response defects.

"severe growth retardation and gross alterations in skeletal development in addition to embryonic melanophore and touch-response defects"
trpm7 is expressed in the mesonephric kidney and mutants develop kidney stones, indicating renal dysfunction.

"We find trpm7 expression in the mesonephric kidney and show that mutants develop kidney stones, indicating renal dysfunction"

PMID:17290233

Cell death of melanophores in zebrafish trpm7 mutant embryos depends on melanin synthesis.

Melanophore death in zebrafish trpm7 mutants occurs by necrosis rather than apoptosis, with abnormal melanosomes and ruptured plasma membranes.

"ultrastructural analysis of dying melanophores in trpm7 mutants reveals abnormal melanosomes and evidence of a ruptured plasma membrane, indicating that cell death occurs by necrosis"
Inhibiting melanin synthesis rescues melanophore survival in trpm7 mutants, indicating Trpm7 is required to detoxify melanin synthesis intermediates.

"inhibition of melanin synthesis largely prevents melanophore cell death in trpm7 mutants"

PMID:20881241

trpm7 regulation of in vivo cation homeostasis and kidney function involves stanniocalcin 1 and fgf23.

trpm7 mutant zebrafish larvae have reduced total magnesium and total calcium, demonstrating an in vivo role for trpm7 in systemic cation homeostasis.

"early larvae exhibit reduced levels of both total magnesium and total calcium"
trpm7 regulates kidney function via stanniocalcin 1 and fgf23; mutants develop kidney stones and elevated fgf23 contributes to stone formation.

"elevated fgf23 expression contributes to kidney stone formation by morpholino knockdown of fgf23 in trpm7 mutants"

PMID:21183474

Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer.

Zebrafish trpm7 (sweetbread) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas due to impaired cell-cycle progression and epithelial growth.

"Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth"
Supplementary Mg2+ partially rescues the exocrine pancreatic defects of trpm7 mutants by repressing socs3a, indicating Trpm7 acts through Mg2+-sensitive Socs3a signaling.

"Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene"

PMID:21832193

TRPM7 is required within zebrafish sensory neurons for the activation of touch-evoked escape behaviors.

TRPM7 acts within sensory neurons to enable touch-evoked escape behaviors, but its kinase activity and divalent-cation selectivity are dispensable for this role.

"TRPM7's kinase activity and selectivity for divalent cations over monovalent cations were dispensable for touch-evoked activation of escape behaviors in zebrafish"
Sensory neurons remain present and mechanosensitive in touchdown (trpm7) mutants, so TRPM7 likely functions in modulating neurotransmitter release at central synapses rather than in mechanosensation or neuron survival.

"sensory neurons were present and capable of responding to tactile stimuli in touchdown mutants, indicating that TRPM7 is not required for sensory neuron survival or mechanosensation"

PMID:23878236

Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity.

TRPM7 is highly expressed in embryonic myocardium and the sinoatrial node and is required for cardiac automaticity; its disruption in zebrafish and mice impairs pacemaking in vivo.

"is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues"
TRPM7 maintains automaticity indirectly by regulating expression of the pacemaker channel gene Hcn4 and its current If, rather than by providing diastolic Ca2+ influx.

"We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression"

PMID:27628598

The coiled-coil domain of zebrafish TRPM7 regulates Mg·nucleotide sensitivity.

The biophysical properties of zebrafish TRPM7 (drTRPM7) closely resemble mammalian TRPM7, and the channel is negatively regulated by intracellular magnesium and Mg·ATP.

"It is negatively regulated by intracellular magnesium (Mg2+), adenosine triphosphate (Mg·ATP) and other polyvalent molecules"
The coiled-coil domain of zebrafish TRPM7 mediates the channel's inhibitory regulation by intracellular magnesium and Mg·ATP.

"the coiled-coil domain of drTRPM7 is involved in the channel's regulation by magnesium (Mg) and Mg·adenosine triphosphate"

PMID:38970357

Zebrafish trpm7 mutants show reduced motility in free movement.

A viable trpm7 mutant allele (I756N substitution in the first transmembrane domain) shows compromised motility with reduced movement distance and velocity.

"trpm7 mutants showed compromised motility with their movement distance shorter than wild-type larvae"
The reduced motility of trpm7 mutants, together with reduced dopaminergic neurons, parallels Parkinson's disease symptoms and links TRPM7 to parkinsonism.

"reduced motility of trpm7 mutants can suggest another similarity between trpm7 phenotypes and Parkinson's disease symptoms"

PMID:9007256

Zebrafish pigmentation mutations and the processes of neural crest development.

A large-scale mutagenesis screen isolated 285 zebrafish pigmentation mutations defining 94 genes affecting neural-crest-derived chromatophores, including the touchtone locus later shown to be trpm7.

"we have isolated 285 mutations affecting all aspects of zebrafish larval pigmentation. By complementation analysis, we define 94 genes"
Many of these pigmentation genes are candidates for chromatophore differentiation and survival, consistent with trpm7's later-identified role in melanophore survival.

"these mutations include strong candidates for genes important in various aspects of chromatophore differentiation and survival"

file:DANRE/trpm7/trpm7-deep-research-falcon.md

Falcon (Edison Scientific) deep research report: trpm7 (Danio rerio, UniProt Q563W7) functional annotation.

TRPM7 is a bifunctional channel-enzyme (chanzyme) comprising a divalent-permeable nonselective cation channel and a cytosolic C-terminal alpha-kinase, matching the UniProt Q563W7 domain architecture and the touchdown/touchtone (tct) zebrafish aliases.

"TRPM7 is often described as a **bifunctional channel-enzyme (chanzyme)**: (i) a **nonselective cation channel** with strong **divalent permeability**, and (ii) a cytosolic **α-kinase** domain that phosphorylates protein substrates on Ser/Thr residues and also autophosphorylates."
TRPM7 is a plasma-membrane cation channel permeable to Mg2+, Ca2+, and Zn2+ with broader divalent permeability, defining its core transport substrate specificity.

"TRPM7 forms a plasma-membrane cation channel permeable to **Mg2+**, **Ca2+**, and **Zn2+**, with broader permeability to other divalent cations"
The channel is constitutively active but strongly regulated; intracellular Mg2+ and Mg-ATP are negative regulators and channel opening requires PIP2.

"**Intracellular Mg2+ and Mg·ATP** act as negative regulators."
The alpha-kinase domain (EC 2.7.11.1) transfers phosphate from ATP to serine/threonine residues of protein substrates and autophosphorylates.

"α-kinase domain transfers phosphate from ATP to **serine/threonine residues** on protein substrates and on TRPM7 itself (autophosphorylation)"
In zebrafish, touch-evoked escape behavior depends on TRPM7 channel activity, whereas kinase activity and strict divalent-over-monovalent selectivity are dispensable, indicating channel/kinase functions are separable.

"at least one core behavioral function (touch-evoked escape) depends on TRPM7 **channel activity**, whereas TRPM7’s **kinase activity** and strict preference for divalents over monovalents were reported to be **dispensable** for that behavior"
Touchdown (trpm7) mutants show a transient touch-evoked escape deficit between 52 and 63 hpf (n = 24 embryos from three clutches), with the defect downstream of intact, tactile-responsive sensory neurons.

"they **do not respond between 52 and 63 hours post-fertilization (hpf)** (reported **n = 24 embryos from three clutches**)"
trpm7 mRNA is broadly expressed in zebrafish with high abundance in pronephric/mesonephric kidney tubules and the corpuscles of Stannius, consistent with a primary role in systemic divalent-cation regulation and renal physiology.

"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"
trpm7 mutants show reduced whole-embryo total magnesium and calcium, kidney stone formation, and altered stc1/fgf23 endocrine programs; fgf23 knockdown reduces kidney stones.

"Mutants also exhibit **kidney stone formation** and altered endocrine programs involving **stanniocalcin 1 (stc1)** and **fgf23**; mechanistically, **fgf23 knockdown reduces kidney stones**"
Melanophore loss in trpm7 mutants occurs by necrosis rather than caspase-dependent apoptosis, and inhibition of melanin synthesis largely prevents melanophore death.

"In **trpm7 mutant embryos**, melanophore loss results from **cell death with necrotic features** (not caspase-dependent apoptosis)."
TRPM7 is a tetrameric plasma-membrane channel; 2023 cryo-EM structures (2.17-2.99 Angstrom) resolved closed and open conformations and druggable agonist/inhibitor pockets.

"Cryo-EM structures in 2023 resolved TRPM7 at **2.17-2.99 Å**"