| Aspect | Summary for zebrafish **trpm7** (UniProt Q563W7) | Key evidence sources |
|---|---|---|
| Verified target identity | **Danio rerio trpm7** corresponds to the zebrafish TRPM7 channel-kinase associated with classic mutant aliases **touchdown/touchtone (tct)** and **cb495**; literature describes a TRP melastatin family cation channel with a **C-terminal serine/threonine α-kinase**, matching UniProt Q563W7 domain architecture. | (pqac-00000004, pqac-00000005, pqac-00000007) |
| Domain architecture | TRPM7 is a **tetrameric plasma-membrane channel** whose subunits contain an **N-terminal TRPM homology region (MHR1-4/NTD)**, **6 transmembrane helices (S1-S6)** with a **pore loop between S5-S6**, a **TRP helix**, **coiled-coil region**, **serine/threonine-rich autophosphorylation/substrate domain**, and a **C-terminal α-kinase catalytic domain**. Structural work places the CTD after the TMD and resolves extensive lipid interactions around the TMD. | (pqac-00000001, pqac-00000008, pqac-00000010, pqac-00000012) |
| Ion permeability / selectivity | TRPM7 is a **divalent-permeable nonselective cation channel** conducting **Mg2+, Ca2+, Zn2+** and additional divalents; broader literature cited in the retrieved evidence also notes permeability to Fe2+, Cu2+, Mn2+, Co2+, Ba2+, Sr2+, Cd2+ and monovalents under some conditions. A reported permeability ranking is **Zn2+ ≈ Ni2+ >> Ba2+ > Co2+ > Mg2+ ≥ Mn2+ ≥ Sr2+ ≥ Cd2+ ≥ Ca2+**; the channel is not permeable to **La3+ or Gd3+**. Single-channel conductance is about **40 pS at ~−70 mV** in the absence of extracellular Mg2+. | (pqac-00000000, pqac-00000001, pqac-00000006, pqac-00000012) |
| Key gating / regulation | Channel activity is **constitutive but strongly regulated**. Important negative regulators include **intracellular Mg2+**, **Mg·ATP**, and **acidic extracellular pH**; activation/opening requires **PIP2**. In whole-cell recordings, extracellular divalents produce **strong outward rectification** via open-channel block. TRPM7 is also reported as sensitive to **pH**, **osmolarity/stretch/swelling**, and receptor pathways that deplete PIP2. | (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000012) |
| Pore / permeation determinants | Acidic vestibule residues help attract permeant cations; **D1054** and **E1052** are highlighted as important for Mg2+/Ca2+ binding/selectivity in human TRPM7, and **D1054A** abolishes proton conductance. 2023 structural work found the closed-to-open transition widens the gate near **N1097/N1098**, with the narrowest open constriction near **Y1085**; **Y1085F/S** are loss-of-function, supporting a key permeation role. | (pqac-00000009, pqac-00000012) |
| Kinase activity | TRPM7 is a **protein kinase EC 2.7.11.1** with a cytosolic **α-kinase** domain that autophosphorylates and phosphorylates serine/threonine residues on downstream targets. Genetic studies indicate channel and kinase functions can be partially separable, with some zebrafish behavioral phenotypes depending mainly on channel function rather than kinase catalytic activity. | (pqac-00000002, pqac-00000005, pqac-00000012) |
| Representative kinase substrates | Reported substrates in the retrieved evidence include **annexin A1/annexin 1**, **myosin II / myosin IIA heavy chain**, **eEF2 kinase**, **STIM2**, and histones after cleavage/nuclear translocation of the kinase fragment in some systems. These data mostly come from non-zebrafish mechanistic studies but are relevant to inferred molecular function of zebrafish Trpm7. | (pqac-00000001, pqac-00000002) |
| Subcellular localization | TRPM7 localizes primarily to the **plasma membrane**, but also to **intracellular tubulovesicular/synaptic vesicle-like compartments**; some evidence describes **acidic glutathione-rich vesicles (M7V)** implicated in Zn2+ storage/release. The kinase fragment has been reported to **translocate to the nucleus** after cleavage in some systems. | (pqac-00000001, pqac-00000002, pqac-00000007) |
| Zebrafish expression | In zebrafish, **trpm7 mRNA is broadly expressed**, with particularly strong expression in **pronephric/mesonephric kidney tubules** and the **corpuscles of Stannius**, consistent with roles in systemic cation homeostasis and renal physiology. | (pqac-00000004) |
| Zebrafish role: ion homeostasis / kidney | Zebrafish mutants show reduced whole-embryo **total magnesium and calcium** by early larval stages, supporting a direct role in organismal divalent-cation balance. Mutants also show **kidney stone formation** and altered endocrine responses involving **stanniocalcin 1 (stc1)** and **fgf23**; **fgf23 knockdown reduces stones**. | (pqac-00000004) |
| Zebrafish role: melanophore survival | **trpm7 homozygous mutants** lose melanophores during embryogenesis; melanophore death shows **necrotic features** rather than caspase-dependent apoptosis. Inhibition of **melanin synthesis largely prevents melanophore death**, suggesting Trpm7 is needed to maintain ionic/metabolic conditions that protect pigment cells from toxic melanin-synthesis intermediates. | (pqac-00000007) |
| Zebrafish role: touch-evoked escape | In **touchdown/tct** mutants, sensory neurons are present and can respond to tactile stimulation, but the animals fail to activate normal escape behavior during a defined developmental window: mutants **do not respond between 52 and 63 hpf**, based on **n = 24 embryos from three clutches**. Rescue experiments indicate **channel activity**, but not kinase activity or strict divalent-over-monovalent selectivity, is required for this behavior. Elevated extracellular divalents can restore escape behavior, consistent with a role in **synaptic transmitter release/modulation**. | (pqac-00000005) |
| Additional zebrafish phenotypes | Beyond pigmentation and touch behavior, zebrafish trpm7 mutants show **impaired growth**, **defective skeletogenesis**, and broader developmental abnormalities consistent with disrupted Mg2+/Ca2+ homeostasis. Maternal transcript contribution likely buffers the earliest stages, contributing to later onset/recovery of some phenotypes. | (pqac-00000004, pqac-00000007) |
| Developmental significance across vertebrates | Comparative evidence supports TRPM7 as essential for **embryogenesis, gastrulation/cell movements, proliferation, and Mg2+ homeostasis**. In vertebrate embryos, channel function is often more critical than kinase catalytic activity for early morphogenesis, which helps interpret zebrafish phenotypes mechanistically. | (pqac-00000003, pqac-00000006) |
| 2023 structural highlight: open-state mechanism | Cryo-EM structures in 2023 resolved TRPM7 at **2.17-2.99 Å**, including a **2.19 Å apo closed state** and open conformations. A gain-of-function mutant (**N1098Q**) produced an open state in which the pore radius at **N1097** increased from **<0.5 Å** to **>2.3 Å**; the narrowest constriction (~**1.4 Å**) is at **Y1085**. Gating involves **S6 lengthening**, **TRP helix shortening/rotation**, and a **π-bulge in S6**. | (pqac-00000008, pqac-00000009, pqac-00000010) |
| 2023 pharmacology highlight: naltriben activation site | The agonist **naltriben (NTB)** binds at an **intersubunit site** formed by the **MHR4/Pre-S1 region** of one subunit and the **α21/α22 loop** of the neighboring subunit. Key coordinating residues include **D670, L671, M741, S744, N752**; mutating these residues weakens NTB activation, defining a tractable activation pocket. | (pqac-00000009, pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000016) |
| 2023 pharmacology highlight: inhibitor site | **VER155008** and **NS8593** were mapped to a **vanilloid-like pocket** in the TMD at the interface of the **S1-S4 domain and pore domain**, contributed by the **N-terminal part of S3**, **C-terminal part of S4**, **S4-S5 linker**, and **TRP helix**. Key residues include **A981, M991, W1111, F1118**. These inhibitors stabilize the **closed state**, supporting TRPM7 druggability. | (pqac-00000008, pqac-00000010, pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000016) |
| Practical application / implementation | Zebrafish **trpm7/tct mutants** are a practical in vivo model for dissecting **divalent-cation homeostasis**, **synaptic transmission**, **pigment-cell survival**, and **renal mineralization**. Recent structural mapping of **NTB**, **VER155008**, and **NS8593** provides a mechanistic framework for using pharmacologic probes in comparative TRPM7 studies, including zebrafish-based functional annotation. | (pqac-00000004, pqac-00000005, pqac-00000008, pqac-00000013) |


*Table: This table condenses the main functional annotation points for zebrafish trpm7/Q563W7, combining zebrafish-specific genetics with broader TRPM7 mechanistic and 2023 structural pharmacology evidence. It is useful as a quick-reference map linking domains, ion/kinase function, localization, phenotypes, and modern druggable sites.*