{"gene":"TRPV6","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2003,"finding":"TRPV6 assembles as a homotetramer (~400 kDa) and can form heterotetramers with TRPV5; heteromeric channels exhibit distinct Ca2+-dependent inactivation, Ba2+ selectivity, and pharmacological block compared to homotetramers.","method":"Sucrose-gradient sedimentation, electrophysiology of concatemeric channels with pore mutant, co-immunoprecipitation from Xenopus oocytes, HEK293 functional assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (sedimentation, electrophysiology, co-IP) in a single study with rigorous controls","pmids":["12574114"],"is_preprint":false},{"year":2003,"finding":"The S100A10–annexin 2 complex binds the conserved C-terminal VATTV motif of TRPV6 (critical residue T600); this interaction is required for routing TRPV6 to the plasma membrane and for channel activity. The T600A mutation redistributes TRPV6 to a sub-plasma-membrane compartment and abolishes current. Annexin 2 siRNA knockdown suppresses TRPV6-mediated currents.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, whole-cell electrophysiology, immunohistochemistry","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution of interaction, mutagenesis of critical residue, functional electrophysiology, siRNA confirmation; multiple orthogonal methods","pmids":["12660155"],"is_preprint":false},{"year":2004,"finding":"Calmodulin (CaM) binds TRPV6 in a Ca2+-dependent manner at multiple sites: the transmembrane domain and consensus CaM-binding motifs in the N-terminus (1-5-10 motif, residues 88-97) and C-terminus (1-8-14 motif, residues 643-656). Ca2+-insensitive CaM mutants significantly reduce TRPV6 Ca2+ and Na+ currents, indicating CaM positively regulates TRPV6 via EF-hands 3 and 4.","method":"GST pull-down, co-immunoprecipitation, overexpression of Ca2+-insensitive CaM mutants, chimeric TRPV6/TRPV5 electrophysiology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical interaction mapping plus functional mutagenesis with chimeras and electrophysiology","pmids":["15123711"],"is_preprint":false},{"year":2006,"finding":"Rab11a directly interacts with TRPV6 (and TRPV5) via a conserved C-terminal stretch; GDP-bound (dominant-negative) Rab11a reduces TRPV6 cell-surface expression and Ca2+ uptake, demonstrating that Rab11a drives TRPV6 trafficking to the apical plasma membrane via direct cargo interaction while GDP-bound.","method":"Yeast two-hybrid, co-immunoprecipitation, cell surface biotinylation, Ca2+ uptake assays, dominant-negative Rab11a coexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed by multiple methods, functional consequence shown with dominant-negative and Ca2+ uptake","pmids":["16354700"],"is_preprint":false},{"year":2006,"finding":"RGS2 binds the N-terminal domain of TRPV6 in a Ca2+-independent manner; overexpression of RGS2 reduces TRPV6 Na+ and Ca2+ currents without affecting plasma membrane expression, indicating direct gating modulation. Deletion of the RGS2 N-terminal domain abolishes this effect. The mechanism is GPCR-independent.","method":"Yeast two-hybrid, GST pull-down, cell surface biotinylation, whole-cell electrophysiology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — interaction mapped to domain level, functional electrophysiology, surface biotinylation ruling out trafficking effect","pmids":["16895908"],"is_preprint":false},{"year":2008,"finding":"Ca2+ influx through TRPV6 activates phospholipase C, causing hydrolysis of PIP2, which in turn contributes to Ca2+-induced inactivation of TRPV6. Dialysis with exogenous PIP2 prevents Ca2+-dependent inactivation; rapamycin-inducible 5-phosphatase depletion of PIP2 inhibits TRPV6; wortmannin (PI4-kinase inhibitor) reduces TRPV6 currents.","method":"Whole-cell patch clamp, excised patch recording, inducible phosphatase system, PIP2 dialysis, wortmannin pharmacology, fura-2 Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal electrophysiological and pharmacological approaches establishing PIP2 as direct activator and its depletion as inactivation mechanism","pmids":["18390907"],"is_preprint":false},{"year":2008,"finding":"Klotho (acting as a beta-glucuronidase) and beta-glucuronidase selectively activate TRPV6 (and TRPV5) by N-oligosaccharide hydrolysis, but have no effect on TRPV4 or TRPM6. Deglycosylation by endoglycosidase-F also stimulates TRPV6 activity.","method":"Ca2+-influx measurements in transfected HEK293 cells treated with klotho, beta-glucuronidase, and endoglycosidase-F","journal":"Nephrology, dialysis, transplantation","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with multiple enzymes and channel specificity controls, single lab","pmids":["18495742"],"is_preprint":false},{"year":2008,"finding":"Cyclophilin B (CypB) associates with TRPV6 in human placenta (co-purified with annexin A2 and CypB); co-expression of CypB with TRPV6 in Xenopus oocytes significantly increases TRPV6-mediated Ca2+ uptake, and this effect is abolished by cyclosporin A (which inhibits CypB peptidyl-prolyl isomerase activity), indicating CypB activates TRPV6 through its enzymatic activity.","method":"Endogenous protein co-purification from placenta, functional Ca2+ uptake in Xenopus oocytes with pharmacological inhibition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — endogenous complex identified and functional effect shown in oocytes with mechanistic inhibitor, single lab","pmids":["18445599"],"is_preprint":false},{"year":2008,"finding":"The annexin 2–S100A10 complex association with TRPV6 is regulated by the cAMP/PKA/calcineurin A (CnA) pathway; forskolin-stimulated PKA activity promotes anx2-S100A10 complex formation, while CnA-dependent dephosphorylation of annexin 2 is required for association with TRPV6 and augments Ca2+ influx in Caco-2 intestinal cells.","method":"Co-immunoprecipitation, 45Ca uptake assays, pharmacological inhibition of PKA and CnA in 16HBE14o- and Caco-2 cells","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical and functional data from two cell lines, but single lab","pmids":["18187190"],"is_preprint":false},{"year":2008,"finding":"TRPV6 mediates maternal-fetal Ca2+ transport in mice; TRPV6 knockout fetuses show 40% lower 45Ca transport from mother, lower fetal blood Ca2+, lower ash weight, and lower amniotic Ca2+. TRPV6 mRNA/protein localizes to intraplacental yolk sac and visceral extraplacental yolk sac, co-localizing with calbindin-D9K.","method":"Trpv6 knockout mice, 45Ca radiotracer transport assay, immunolocalization, RT-PCR","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with quantitative radiotracer readout and localization data, strong evidence","pmids":["18348695"],"is_preprint":false},{"year":2011,"finding":"TRPV6 is expressed in the apical membrane of epididymal epithelium (not in sperm); mice homozygous for the pore-dead D541A mutation have 10-fold higher Ca2+ in cauda epididymal fluid, 7-8-fold reduced Ca2+ absorption through epididymal epithelium, and severely impaired male fertility with reduced sperm motility and viability despite intact spermatogenesis.","method":"Trpv6(D541A/D541A) knock-in mice, Ca2+ measurement of epididymal fluid, Ca2+ absorption assay, fertility testing, immunolocalization","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — channel-dead knock-in with quantitative Ca2+ absorption phenotype; mechanistically links TRPV6 pore function to epididymal Ca2+ homeostasis and male fertility","pmids":["21540454"],"is_preprint":false},{"year":2011,"finding":"PIP2 is a direct activator of TRPV6; intracellular ATP maintains TRPV6 activity indirectly by serving as substrate for type III PI4 kinases to resynthesize PIP2. In excised patches, MgATP-dependent reactivation is blocked by PI4K inhibitors; PIP2 (but not PI4P) activates reconstituted TRPV6 in planar lipid bilayers.","method":"Excised inside-out patch clamp, planar lipid bilayer reconstitution of purified TRPV6, pharmacological PI4K inhibition","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of purified channel in bilayers plus excised patch pharmacology establishes direct PIP2 activation","pmids":["21810903"],"is_preprint":false},{"year":2013,"finding":"In vivo TRPV6 translation initiates at a non-AUG codon (ACG upstream of annotated AUG), producing an N-terminally extended protein 40 residues longer. The extended N-terminus increases plasma membrane trafficking and provides an additional scaffold for channel assembly, while the channel's biophysical properties remain similar to the shorter form.","method":"Mass spectrometry of endogenous protein, mutagenesis of initiation codons, cell surface biotinylation, electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — endogenous protein identified by MS, functional trafficking consequence shown by biotinylation and electrophysiology","pmids":["23612980"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of rat TRPV6 at 3.25 Å reveals Ca2+ selectivity determined by direct coordination by a ring of aspartate side chains in the selectivity filter; intracellular domains form an 'intracellular skirt' involved in allosteric modulation; cation-binding sites at the pore axis and extracellular vestibule define the Ca2+ permeation mechanism.","method":"X-ray crystallography at 3.25 Å resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution crystal structure with identified ion-binding sites; foundational structural paper","pmids":["27296226"],"is_preprint":false},{"year":2017,"finding":"Cryo-EM structures of human TRPV6 in open and closed states reveal that channel opening involves an α-to-π helical transition in the pore-lining S6 helix at an alanine hinge below the selectivity filter, causing S6 to bend and rotate (iris-like gating). The selectivity filter adopts similar conformations in both states. PIP2 increases open probability.","method":"Cryo-electron microscopy, electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structures of both open and closed states, defining gating mechanism","pmids":["29258289"],"is_preprint":false},{"year":2018,"finding":"2-APB inhibits TRPV6 by binding in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle and inducing channel closure by modulating protein-lipid interactions; comparison of wild-type and high-affinity Y467A mutant structures defined the binding site.","method":"Crystal structures and cryo-EM of TRPV6-2-APB complexes, mutagenesis, functional electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — structural determination of inhibitor-bound complex combined with mutagenesis and functional validation","pmids":["29941865"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of TRPV6 inactivated by calmodulin (CaM) shows 1:1 stoichiometry (one CaM per TRPV6 tetramer) with CaM lobes in a head-to-tail arrangement; the CaM C-terminal lobe plugs the channel pore by inserting K115 into a tetra-tryptophan cage at the intracellular entrance via a cation-π interaction.","method":"Cryo-electron microscopy, functional electrophysiology","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution inactivated-state structure revealing unique plugging mechanism","pmids":["30116787"],"is_preprint":false},{"year":2010,"finding":"Nedd4-2 ubiquitinates TRPV6 and reduces its protein abundance and Ca2+ influx primarily via proteasomal (not lysosomal) degradation without significantly altering internalization rate; WW1/WW2 domains of Nedd4-2 interact with TRPV6 termini and serve as a molecular switch limiting ubiquitination by the HECT domain.","method":"Xenopus oocyte expression, ubiquitination assays, proteasome/lysosome inhibitors, co-immunoprecipitation, Ca2+ uptake assays, WW domain mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical ubiquitination assay, mechanistic domain mutagenesis, and functional Ca2+ uptake with multiple inhibitors","pmids":["20843805"],"is_preprint":false},{"year":2007,"finding":"TRPV6 mediates Ca2+ entry in LNCaP prostate cancer cells; TRPV6-mediated Ca2+ uptake activates the NFAT transcription factor downstream; TRPV6 knockdown reduces proliferation rate, S-phase accumulation, and PCNA expression, and decreases apoptosis resistance.","method":"siRNA knockdown, Ca2+ imaging, cell cycle analysis, PCNA western blot, NFAT reporter assay in LNCaP cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple defined cellular phenotypes and downstream signaling readout","pmids":["17533368"],"is_preprint":false},{"year":2014,"finding":"TRPV6 translocates to the plasma membrane in prostate cancer cells via an Orai1/TRPC1-mediated Ca2+/Annexin I/S100A11 pathway; TRPV6-overexpressing tumors show enhanced proliferation and apoptosis resistance in xenograft and bone metastasis models.","method":"Co-immunoprecipitation, calcium imaging, cell surface biotinylation, siRNA knockdown, xenograft mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway defined by co-IP and functional assays, in vivo confirmation, but mechanistic detail of trafficking remains partially inferred","pmids":["25172921"],"is_preprint":false},{"year":2009,"finding":"SGK1 and PKB/Akt increase TRPV6 activity and plasma membrane abundance in Xenopus oocytes; PIKfyve (phosphorylated by SGK1 at S318) further augments TRPV6 activity and membrane expression when co-expressed with active SGK1, identifying a SGK1-PIKfyve axis regulating TRPV6 surface expression.","method":"Xenopus oocyte electrophysiology, immunohistochemistry, western blotting with constitutively active kinase mutants","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional electrophysiology with kinase mutants, membrane abundance confirmed, single lab","pmids":["20041238"],"is_preprint":false},{"year":2019,"finding":"CaSR activation in the basolateral membrane of intestinal epithelium directly attenuates TRPV6-dependent Ca2+ absorption via a phospholipase C-dependent mechanism; cinacalcet inhibits Ca2+ flux through TRPV6 when co-expressed with CaSR in Xenopus oocytes, and this effect is absent in Trpv6(D541A) mice.","method":"Ussing chamber Ca2+ flux assays, Trpv6D541A mice, Xenopus oocyte co-expression, PLC inhibitor (U73122)","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model combined with oocyte co-expression and pharmacological pathway dissection","pmids":["31013259"],"is_preprint":false},{"year":2008,"finding":"Nipsnap1 associates with TRPV6 (identified by bioinformatics and pull-down) and abolishes TRPV6 currents in electrophysiological recordings without affecting TRPV6 plasma membrane expression, suggesting direct gating inhibition at the membrane.","method":"Bioinformatics, GST pull-down, electrophysiology, cell surface biotinylation in HEK293 cells","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional electrophysiology with biotinylation ruling out trafficking, but interaction not confirmed by co-IP","pmids":["18392847"],"is_preprint":false},{"year":2004,"finding":"PTP1B interacts with TRPV6 in vivo (bimolecular fluorescence complementation, co-immunoprecipitation); Src kinase phosphorylates TRPV6 tyrosine residues which are dephosphorylated by PTP1B; inhibition of tyrosine phosphatases with DMHV increases TRPV6-mediated Ca2+ entry following store depletion, and this effect is abolished by Src inhibition.","method":"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, Ca2+ imaging, phosphatase and kinase inhibitors in HEK293 cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo interaction confirmed by two methods, functional phosphorylation consequence shown, single lab","pmids":["15894168"],"is_preprint":false},{"year":2012,"finding":"Numb1 interacts with TRPV6 via TRPV6 C-terminal D716 and Numb1 R434; Numb1 overexpression decreases cytosolic Ca2+ in TRPV6-transfected HEK293 cells; Numb1 mutant lacking TRPV6-binding capacity fails to inhibit TRPV6 activity; Numb knockdown in MCF-7 cells increases TRPV6 expression, Ca2+ influx, and proliferation.","method":"Co-immunoprecipitation, FRET, site-directed mutagenesis, Ca2+ imaging, siRNA knockdown in HEK293 and MCF-7 cells","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction mapped to specific residues with FRET confirmation, functional consequence by mutagenesis and siRNA","pmids":["23140583"],"is_preprint":false},{"year":2016,"finding":"TRPV6 is constitutively active in epididymal principal cells and is functionally coupled to TMEM16A (a Ca2+-activated Cl- channel); Ca2+ entry through TRPV6-like channels drives Ca2+-activated chloride conductance; removal of extracellular Ca2+ or La3+ block attenuates both conductances; both proteins co-localize at the apical membrane.","method":"Patch clamp on isolated rat cauda epididymal principal cells, pharmacology, in vivo tubule perfusion, co-localization by immunofluorescence, RT-PCR","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology in native cells with pharmacological dissection and in vivo Ca2+ flux, functional coupling established","pmids":["27481714"],"is_preprint":false},{"year":2019,"finding":"TRPV6 mediates constitutive Ca2+ influx in epithelial cells and maintains cellular quiescence by activating PP2A, which suppresses IGF-mediated Akt-Tor and Erk signaling; genetic deletion or pharmacological block of Trpv6 causes epithelial cells to re-enter the cell cycle in zebrafish; reintroduction of channel-competent but not channel-dead Trpv6 restores quiescence.","method":"Trpv6 genetic knockout in zebrafish, pharmacological blockade, Ca2+ imaging, PP2A activity assay, IGF signaling western blot, human colon carcinoma cell validation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological loss-of-function with channel-dead rescue, mechanistic pathway (PP2A→IGF signaling) identified in vivo and in vitro","pmids":["31526479"],"is_preprint":false},{"year":2020,"finding":"TRPV6 activation is autoinhibited by intramolecular interactions: the S4-S5 linker interacts with the C-terminal TRP helix (Arg470:Trp593) and the N-terminal pre-S1 helix interacts with the TRP helix (Trp321:Ile597); PIP2 binds three cationic residues in S5 or C-terminus to disrupt both interactions and activate the channel. Disruption of either interaction by mutation or blocking peptides activates TRPV6.","method":"Site-directed mutagenesis, blocking peptides, electrophysiology, molecular modeling","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis and peptide competition with functional electrophysiological readout, single lab","pmids":["32829285"],"is_preprint":false},{"year":2022,"finding":"TRPV6 is required for alcohol-induced intestinal Ca2+ influx, tight junction disruption, and gut barrier dysfunction; ethanol and acetaldehyde directly activate TRPV6 ionic currents; photoaffinity labeling identifies a histidine in TRPV6 as a potential alcohol-binding site; substitution of this histidine and a nearby arginine reduces ethanol-activated currents; Trpv6-/- mice are resistant to alcohol-induced barrier dysfunction.","method":"Patch clamp in Caco-2 cells, intestinal organoids, Trpv6-/- mice, photoaffinity labeling (3-azibutanol), site-directed mutagenesis, TEER assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — identification of binding site by photoaffinity labeling plus mutagenesis, in vivo genetic confirmation, multiple orthogonal approaches","pmids":["35705057"],"is_preprint":false},{"year":2021,"finding":"TRPV6 promotes breast cancer metastasis by activating NFATC2 through increased phosphorylation of NFATC2IP at Ser204 (with CDK5 as a candidate kinase), leading to NFATC2-driven upregulation of ADAMTS6 and enhanced cell migration.","method":"TRPV6 overexpression/knockdown, phospho-western blot, siRNA, NFATC2 reporter, migration assays in breast cancer cells","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway mechanistically defined with multiple molecular readouts, but CDK5 involvement inferred, single lab","pmids":["34265397"],"is_preprint":false},{"year":2019,"finding":"Maternal TRPV6 in trophoblasts of the fetal labyrinth and yolk sac mediates Ca2+ uptake required for embryonic bone development; Trpv6 deficiency in the mother reduces Ca2+ content in placenta and embryo, causes smaller embryos with shorter, less calcified femurs, and impaired cortical bone microarchitecture persisting to adulthood; re-expression of channel-competent TRPV6 rescues the phenotype.","method":"Trpv6 knockout mice, embryo Ca2+ content measurement, trophoblast Ca2+ uptake assay, micro-CT, histomorphometry, immunolocalization","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — in vivo maternal-specific loss-of-function with quantitative Ca2+ uptake and bone phenotype, channel-competence rescue","pmids":["30786075"],"is_preprint":false}],"current_model":"TRPV6 is a constitutively active, highly Ca2+-selective tetrameric ion channel that mediates apical Ca2+ entry in epithelial tissues (intestine, kidney, placenta, epididymis); its selectivity filter is formed by a ring of aspartate residues, its gating involves an α-to-π helical transition in S6 at an alanine hinge, and its activity is tightly regulated by: (1) Ca2+-dependent CaM binding that plugs the pore intracellularly via a cation-π interaction, (2) PIP2, which relieves autoinhibitory S4-S5 linker/TRP-helix interactions to activate the channel, (3) ubiquitination by Nedd4-2 promoting proteasomal degradation, (4) trafficking to the plasma membrane via Rab11a and the S100A10-annexin 2 complex (which requires the C-terminal VATTV motif), (5) allosteric modulation by RGS2, Nipsnap1, cyclophilin B, Numb1, and PTP1B/Src, and (6) transcriptional upregulation by 1,25-dihydroxyvitamin D3; downstream of Ca2+ entry, TRPV6 activates NFAT signaling to control cell proliferation and, via PP2A, suppresses IGF-Akt-Tor/Erk signaling to maintain epithelial quiescence."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing the oligomeric state: TRPV6 was shown to assemble as a homotetramer (and heterotetramerize with TRPV5), resolving the stoichiometry of the functional channel and demonstrating that subunit composition tunes inactivation and selectivity properties.","evidence":"Sucrose-gradient sedimentation, concatemeric pore-mutant electrophysiology, and co-IP in Xenopus oocytes/HEK293 cells","pmids":["12574114"],"confidence":"High","gaps":["No high-resolution structure yet; inter-subunit interfaces undefined","Physiological relevance of TRPV5/V6 heteromers in native tissues not established"]},{"year":2003,"claim":"Identifying a trafficking mechanism: the S100A10–annexin 2 complex was found to bind TRPV6's C-terminal VATTV motif (critical residue T600) and was required for plasma membrane delivery and channel activity, establishing the first defined route for TRPV6 surface expression.","evidence":"Yeast two-hybrid, GST pull-down, site-directed mutagenesis (T600A), siRNA knockdown, electrophysiology","pmids":["12660155"],"confidence":"High","gaps":["The vesicular compartment where S100A10–annexin 2 engages TRPV6 was not identified","Whether the VATTV motif is sufficient for trafficking in native epithelia was not tested"]},{"year":2004,"claim":"Defining calmodulin as a Ca²⁺-dependent regulator: CaM was shown to bind TRPV6 at N- and C-terminal motifs in a Ca²⁺-dependent manner, and Ca²⁺-insensitive CaM mutants reduced channel currents, establishing CaM as a direct modulator — though whether it acts as activator or inactivator was not yet resolved at the structural level.","evidence":"GST pull-down, co-IP, CaM mutant overexpression, electrophysiology in HEK293 cells","pmids":["15123711"],"confidence":"High","gaps":["Structural basis of CaM–TRPV6 interaction and stoichiometry unknown at this stage","Relative contributions of N- vs. C-terminal CaM binding sites not dissected"]},{"year":2004,"claim":"Identifying tyrosine phosphorylation as a regulatory switch: Src was shown to phosphorylate TRPV6, and PTP1B to dephosphorylate it, with net phosphorylation increasing Ca²⁺ entry — establishing a kinase/phosphatase cycle modulating channel activity.","evidence":"BiFC, co-IP, Ca²⁺ imaging with Src and phosphatase inhibitors in HEK293 cells","pmids":["15894168"],"confidence":"Medium","gaps":["Specific tyrosine residue(s) phosphorylated were not identified","In vivo relevance of Src/PTP1B regulation not demonstrated"]},{"year":2006,"claim":"Identifying Rab11a as a direct trafficking partner: Rab11a was shown to bind TRPV6's C-terminus and drive its apical membrane delivery, with dominant-negative Rab11a reducing surface expression and Ca²⁺ uptake — placing TRPV6 in the Rab11a recycling endosome pathway.","evidence":"Yeast two-hybrid, co-IP, surface biotinylation, Ca²⁺ uptake with dominant-negative Rab11a","pmids":["16354700"],"confidence":"High","gaps":["Whether Rab11a acts on TRPV6 via direct cargo binding or an adaptor intermediate was not fully resolved","Relationship between Rab11a and S100A10–annexin 2 trafficking routes not clarified"]},{"year":2006,"claim":"Discovering GPCR-independent gating modulation by RGS2: RGS2 was found to bind the TRPV6 N-terminus and inhibit currents without reducing surface expression, identifying a non-canonical, G-protein-independent role for an RGS protein as a direct channel gating modulator.","evidence":"Yeast two-hybrid, GST pull-down, surface biotinylation, electrophysiology in HEK293 cells","pmids":["16895908"],"confidence":"High","gaps":["Mechanism by which RGS2 N-terminal domain alters gating conformations unknown","Physiological stimulus controlling RGS2–TRPV6 interaction not identified"]},{"year":2007,"claim":"Linking TRPV6 Ca²⁺ entry to proliferative signaling: TRPV6 knockdown in prostate cancer cells reduced NFAT activation, cell proliferation, and apoptosis resistance, establishing that TRPV6-mediated Ca²⁺ influx drives a Ca²⁺–NFAT signaling axis controlling cell cycle progression.","evidence":"siRNA knockdown, NFAT reporter assay, cell cycle analysis, Ca²⁺ imaging in LNCaP cells","pmids":["17533368"],"confidence":"High","gaps":["Which NFAT isoform is the primary effector was not defined","Whether TRPV6-NFAT signaling occurs in normal epithelia or is cancer-specific was unclear"]},{"year":2008,"claim":"Establishing PIP₂ as a direct channel activator and its hydrolysis as an inactivation mechanism: PIP₂ dialysis prevented Ca²⁺-dependent inactivation, PIP₂ depletion by inducible phosphatase inhibited TRPV6, and Ca²⁺ influx itself drove PIP₂ hydrolysis via PLC, revealing a negative feedback loop.","evidence":"Patch clamp, inducible 5-phosphatase, PIP₂ dialysis, wortmannin, fura-2 imaging","pmids":["18390907"],"confidence":"High","gaps":["PIP₂ binding site on TRPV6 not yet mapped","Relative contribution of PIP₂ depletion vs. CaM binding to inactivation not quantified"]},{"year":2008,"claim":"Demonstrating TRPV6's physiological role in maternal–fetal Ca²⁺ transport: Trpv6 knockout fetuses showed 40% reduced placental ⁴⁵Ca transport, lower blood Ca²⁺, and reduced mineralization, establishing TRPV6 as the rate-limiting apical entry step for transplacental calcium delivery.","evidence":"Trpv6 knockout mice, ⁴⁵Ca radiotracer transport, immunolocalization in yolk sac/placenta","pmids":["18348695"],"confidence":"High","gaps":["Whether compensatory mechanisms partially sustain Ca²⁺ transport in knockouts was not dissected","The vitamin D-dependent transcriptional regulation of placental TRPV6 was not assessed"]},{"year":2010,"claim":"Identifying Nedd4-2-mediated ubiquitination as a degradation pathway: Nedd4-2 was shown to ubiquitinate TRPV6 and target it for proteasomal (not lysosomal) degradation, with WW domains acting as a molecular switch — establishing ubiquitin-dependent protein turnover as a key mechanism limiting TRPV6 abundance.","evidence":"Ubiquitination assays, proteasome/lysosome inhibitors, WW domain mutagenesis, Ca²⁺ uptake in Xenopus oocytes","pmids":["20843805"],"confidence":"High","gaps":["Specific ubiquitinated lysine residues on TRPV6 not mapped","Physiological signals triggering Nedd4-2 engagement not identified"]},{"year":2011,"claim":"Proving TRPV6 pore function is essential for epididymal Ca²⁺ absorption and male fertility: Trpv6(D541A) knock-in mice had massively elevated epididymal fluid Ca²⁺ and severely impaired sperm motility and fertility, directly linking the channel's ion-conducting pore to a specific physiological outcome.","evidence":"Channel-dead D541A knock-in mice, epididymal fluid Ca²⁺ measurement, Ca²⁺ absorption assay, fertility testing","pmids":["21540454"],"confidence":"High","gaps":["Whether TRPV6 has non-conducting roles in epididymal cells was not tested","Downstream Ca²⁺-dependent effectors in epididymal epithelium not identified"]},{"year":2011,"claim":"Demonstrating direct PIP₂ activation in a reconstituted system: purified TRPV6 in planar lipid bilayers was activated by PIP₂ but not PI4P, and MgATP-dependent reactivation required PI4K activity, proving that PIP₂ is a direct, sufficient lipid activator rather than acting through an intermediate.","evidence":"Purified TRPV6 reconstituted in planar lipid bilayers, excised patch clamp, PI4K inhibitors","pmids":["21810903"],"confidence":"High","gaps":["PIP₂ binding site still not structurally defined","Lipid species specificity beyond PIP₂/PI4P not tested"]},{"year":2016,"claim":"Solving the atomic structure: the crystal structure of TRPV6 at 3.25 Å revealed how aspartate side chains in the selectivity filter directly coordinate Ca²⁺ ions, defined the intracellular 'skirt' domain architecture, and identified cation-binding sites along the permeation pathway — providing the structural framework for understanding selectivity and gating.","evidence":"X-ray crystallography at 3.25 Å resolution (rat TRPV6)","pmids":["27296226"],"confidence":"High","gaps":["Only a single conformational state captured","PIP₂ and CaM binding sites not visualized"]},{"year":2017,"claim":"Defining the gating mechanism: cryo-EM structures in open and closed states revealed that gating proceeds through an α-to-π helical transition at an alanine hinge in S6, causing iris-like rotation — a novel gating mechanism for TRP channels.","evidence":"Cryo-EM of human TRPV6 in open/closed states, electrophysiology","pmids":["29258289"],"confidence":"High","gaps":["Intermediate gating states not captured","How PIP₂ binding allosterically triggers the S6 transition not resolved at atomic level"]},{"year":2018,"claim":"Revealing the CaM-mediated inactivation mechanism at atomic resolution: cryo-EM showed that one CaM binds per TRPV6 tetramer in a head-to-tail arrangement and directly plugs the pore by inserting CaM K115 into a tetra-tryptophan cage via cation–π interaction — a unique channel inactivation mechanism.","evidence":"Cryo-EM of CaM-bound TRPV6, electrophysiology","pmids":["30116787"],"confidence":"High","gaps":["How CaM initially docks to the channel before pore insertion is unknown","Whether CaM-mediated inactivation and PIP₂ depletion are cooperative or independent processes not determined"]},{"year":2018,"claim":"Structural basis of pharmacological inhibition: 2-APB was shown to bind in the S1–S4 bundle cytoplasmic pocket, modulating protein–lipid interactions to close the channel — providing a template for structure-based drug design targeting TRPV6.","evidence":"Crystal structures and cryo-EM of TRPV6–2-APB complexes, Y467A mutagenesis, electrophysiology","pmids":["29941865"],"confidence":"High","gaps":["Whether the 2-APB site overlaps with endogenous modulators not tested","Selectivity of 2-APB for TRPV6 over other TRP channels not structurally explained"]},{"year":2019,"claim":"Establishing TRPV6 as a quiescence signal via PP2A: constitutive Ca²⁺ influx through TRPV6 was shown to activate PP2A, which suppresses IGF–Akt–Erk signaling to maintain epithelial quiescence in zebrafish, with channel-dead rescue failing to restore quiescence — revealing that TRPV6's growth-suppressive role is ion-conductance-dependent.","evidence":"Trpv6 knockout zebrafish, pharmacological blockade, channel-dead rescue, PP2A activity assay, IGF pathway western blots, human colon carcinoma validation","pmids":["31526479"],"confidence":"High","gaps":["How Ca²⁺ activates PP2A downstream of TRPV6 is mechanistically undefined","Whether the quiescence function is conserved across all TRPV6-expressing mammalian epithelia not demonstrated"]},{"year":2019,"claim":"Defining a basolateral-to-apical feedback loop: CaSR activation on the basolateral membrane was shown to attenuate apical TRPV6-mediated Ca²⁺ absorption via PLC-dependent PIP₂ depletion, with confirmation in Trpv6(D541A) mice — integrating PIP₂ regulation with systemic Ca²⁺-sensing physiology.","evidence":"Ussing chamber assays, Trpv6D541A mice, CaSR/TRPV6 co-expression in oocytes, PLC inhibitor","pmids":["31013259"],"confidence":"High","gaps":["Whether CaSR-TRPV6 coupling occurs in tissues beyond intestine not tested","Quantitative contribution of PIP₂ depletion vs. other PLC products (DAG, IP₃) not dissected"]},{"year":2020,"claim":"Mapping the PIP₂-dependent autoinhibition mechanism: specific intramolecular contacts (S4-S5 linker:TRP helix, pre-S1:TRP helix) were shown to hold TRPV6 in an autoinhibited state, with PIP₂ disrupting these interactions to activate the channel — providing a molecular model for how PIP₂ allosterically gates TRPV6.","evidence":"Site-directed mutagenesis, blocking peptides, electrophysiology, molecular modeling","pmids":["32829285"],"confidence":"Medium","gaps":["No direct structural visualization of PIP₂ in the binding site","Blocking peptide approach requires validation with purified components"]},{"year":2022,"claim":"Discovering ethanol as a direct TRPV6 activator: ethanol and acetaldehyde were shown to activate TRPV6 currents, and photoaffinity labeling identified a histidine as part of the alcohol-binding site; Trpv6⁻/⁻ mice were resistant to alcohol-induced gut barrier dysfunction — establishing TRPV6 as a molecular mediator of alcohol-induced epithelial injury.","evidence":"Patch clamp, photoaffinity labeling, site-directed mutagenesis, Trpv6⁻/⁻ mice, TEER assay, intestinal organoids","pmids":["35705057"],"confidence":"High","gaps":["Complete alcohol-binding pocket not structurally resolved","Whether alcohol-induced TRPV6 activation contributes to Ca²⁺ malabsorption in alcoholism not tested"]},{"year":null,"claim":"Key open questions include: the complete structural basis of PIP₂ binding and how it allosterically couples to the S6 gating transition; the mechanism by which TRPV6-dependent Ca²⁺ activates PP2A; whether the NFAT-driven proliferative and PP2A-driven quiescence programs are cell-type-specific or co-exist; and the full spectrum of post-translational modifications (phosphorylation sites, glycosylation) regulating TRPV6 in native epithelia.","evidence":"","pmids":[],"confidence":"Low","gaps":["PIP₂ binding site not structurally resolved on TRPV6","Ca²⁺-to-PP2A coupling mechanism unknown","Integration of NFAT and PP2A signaling arms not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,5,10,11,13,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,11,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,10,12,25]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[9,10,11,13,14,28]}],"complexes":["TRPV6 homotetramer","TRPV5/TRPV6 heterotetramer"],"partners":["TRPV5","ANXA2","S100A10","RAB11A","CALM1","RGS2","NEDD4L","NUMB"],"other_free_text":[]},"mechanistic_narrative":"TRPV6 is a constitutively active, highly Ca²⁺-selective tetrameric channel that mediates apical Ca²⁺ entry in absorptive epithelia of the intestine, kidney, placenta, and epididymis, linking transcellular calcium transport to systemic mineral homeostasis, male fertility, and fetal skeletal development. Its selectivity filter is formed by a ring of aspartate residues coordinating Ca²⁺ ions, and channel gating involves an α-to-π helical transition at an alanine hinge in S6; Ca²⁺-dependent inactivation is mediated by calmodulin, which binds 1:1 per tetramer and plugs the intracellular pore entrance via a cation–π interaction, and by PIP₂ hydrolysis, whereas PIP₂ binding activates the channel by disrupting autoinhibitory S4-S5 linker/TRP-helix interactions [PMID:27296226, PMID:29258289, PMID:30116787, PMID:18390907, PMID:32829285]. Channel surface expression is controlled by Rab11a-dependent trafficking, the S100A10–annexin 2 complex (requiring the C-terminal VATTV motif), and Nedd4-2-mediated ubiquitination targeting TRPV6 for proteasomal degradation, while gating is further modulated by RGS2, Nipsnap1, cyclophilin B, Numb1, and Src/PTP1B-dependent tyrosine phosphorylation [PMID:12660155, PMID:16354700, PMID:20843805, PMID:16895908]. Downstream of Ca²⁺ entry, TRPV6 activates NFAT signaling to promote cell proliferation and, via PP2A, suppresses IGF–Akt–Erk signaling to maintain epithelial quiescence; loss of TRPV6 function in vivo impairs maternal–fetal Ca²⁺ transport and bone mineralization, disrupts epididymal Ca²⁺ reabsorption causing male infertility, and confers resistance to alcohol-induced gut barrier dysfunction [PMID:17533368, PMID:31526479, PMID:18348695, PMID:21540454, PMID:35705057]."},"prefetch_data":{"uniprot":{"accession":"Q9H1D0","full_name":"Transient receptor potential cation channel subfamily V member 6","aliases":["CaT-like","CaT-L","Calcium transport protein 1","CaT1","Epithelial calcium channel 2","ECaC2"],"length_aa":765,"mass_kda":87.3,"function":"Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11248124, PubMed:11278579, PubMed:15184369, PubMed:23612980, PubMed:29258289). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H1D0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPV6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPV6","total_profiled":1310},"omim":[{"mim_id":"618188","title":"HYPERPARATHYROIDISM, TRANSIENT NEONATAL; HRPTTN","url":"https://www.omim.org/entry/618188"},{"mim_id":"616252","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 2; TCAF2","url":"https://www.omim.org/entry/616252"},{"mim_id":"616251","title":"TRPM8 CHANNEL-ASSOCIATED FACTOR 1; TCAF1","url":"https://www.omim.org/entry/616251"},{"mim_id":"606680","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 6; TRPV6","url":"https://www.omim.org/entry/606680"},{"mim_id":"606679","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 5; TRPV5","url":"https://www.omim.org/entry/606679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":36.4},{"tissue":"prostate","ntpm":22.1},{"tissue":"salivary gland","ntpm":65.3}],"url":"https://www.proteinatlas.org/search/TRPV6"},"hgnc":{"alias_symbol":["CaT1"],"prev_symbol":["ECAC2"]},"alphafold":{"accession":"Q9H1D0","domains":[{"cath_id":"1.25.40.20","chopping":"76-276","consensus_level":"medium","plddt":92.9338,"start":76,"end":276},{"cath_id":"1.10.287.70","chopping":"522-644","consensus_level":"high","plddt":89.785,"start":522,"end":644},{"cath_id":"1.20.120","chopping":"354-396_410-510","consensus_level":"high","plddt":90.6865,"start":354,"end":510}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1D0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1D0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H1D0-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPV6","jax_strain_url":"https://www.jax.org/strain/search?query=TRPV6"},"sequence":{"accession":"Q9H1D0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H1D0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H1D0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H1D0"}},"corpus_meta":[{"pmid":"18248592","id":"PMC_18248592","title":"AtMKK1 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heteromeric channels exhibit distinct Ca2+-dependent inactivation, Ba2+ selectivity, and pharmacological block compared to homotetramers.\",\n      \"method\": \"Sucrose-gradient sedimentation, electrophysiology of concatemeric channels with pore mutant, co-immunoprecipitation from Xenopus oocytes, HEK293 functional assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (sedimentation, electrophysiology, co-IP) in a single study with rigorous controls\",\n      \"pmids\": [\"12574114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The S100A10–annexin 2 complex binds the conserved C-terminal VATTV motif of TRPV6 (critical residue T600); this interaction is required for routing TRPV6 to the plasma membrane and for channel activity. The T600A mutation redistributes TRPV6 to a sub-plasma-membrane compartment and abolishes current. Annexin 2 siRNA knockdown suppresses TRPV6-mediated currents.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, whole-cell electrophysiology, immunohistochemistry\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of interaction, mutagenesis of critical residue, functional electrophysiology, siRNA confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"12660155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Calmodulin (CaM) binds TRPV6 in a Ca2+-dependent manner at multiple sites: the transmembrane domain and consensus CaM-binding motifs in the N-terminus (1-5-10 motif, residues 88-97) and C-terminus (1-8-14 motif, residues 643-656). Ca2+-insensitive CaM mutants significantly reduce TRPV6 Ca2+ and Na+ currents, indicating CaM positively regulates TRPV6 via EF-hands 3 and 4.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, overexpression of Ca2+-insensitive CaM mutants, chimeric TRPV6/TRPV5 electrophysiology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical interaction mapping plus functional mutagenesis with chimeras and electrophysiology\",\n      \"pmids\": [\"15123711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab11a directly interacts with TRPV6 (and TRPV5) via a conserved C-terminal stretch; GDP-bound (dominant-negative) Rab11a reduces TRPV6 cell-surface expression and Ca2+ uptake, demonstrating that Rab11a drives TRPV6 trafficking to the apical plasma membrane via direct cargo interaction while GDP-bound.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, cell surface biotinylation, Ca2+ uptake assays, dominant-negative Rab11a coexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by multiple methods, functional consequence shown with dominant-negative and Ca2+ uptake\",\n      \"pmids\": [\"16354700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RGS2 binds the N-terminal domain of TRPV6 in a Ca2+-independent manner; overexpression of RGS2 reduces TRPV6 Na+ and Ca2+ currents without affecting plasma membrane expression, indicating direct gating modulation. Deletion of the RGS2 N-terminal domain abolishes this effect. The mechanism is GPCR-independent.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, cell surface biotinylation, whole-cell electrophysiology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — interaction mapped to domain level, functional electrophysiology, surface biotinylation ruling out trafficking effect\",\n      \"pmids\": [\"16895908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ca2+ influx through TRPV6 activates phospholipase C, causing hydrolysis of PIP2, which in turn contributes to Ca2+-induced inactivation of TRPV6. Dialysis with exogenous PIP2 prevents Ca2+-dependent inactivation; rapamycin-inducible 5-phosphatase depletion of PIP2 inhibits TRPV6; wortmannin (PI4-kinase inhibitor) reduces TRPV6 currents.\",\n      \"method\": \"Whole-cell patch clamp, excised patch recording, inducible phosphatase system, PIP2 dialysis, wortmannin pharmacology, fura-2 Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal electrophysiological and pharmacological approaches establishing PIP2 as direct activator and its depletion as inactivation mechanism\",\n      \"pmids\": [\"18390907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Klotho (acting as a beta-glucuronidase) and beta-glucuronidase selectively activate TRPV6 (and TRPV5) by N-oligosaccharide hydrolysis, but have no effect on TRPV4 or TRPM6. Deglycosylation by endoglycosidase-F also stimulates TRPV6 activity.\",\n      \"method\": \"Ca2+-influx measurements in transfected HEK293 cells treated with klotho, beta-glucuronidase, and endoglycosidase-F\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with multiple enzymes and channel specificity controls, single lab\",\n      \"pmids\": [\"18495742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cyclophilin B (CypB) associates with TRPV6 in human placenta (co-purified with annexin A2 and CypB); co-expression of CypB with TRPV6 in Xenopus oocytes significantly increases TRPV6-mediated Ca2+ uptake, and this effect is abolished by cyclosporin A (which inhibits CypB peptidyl-prolyl isomerase activity), indicating CypB activates TRPV6 through its enzymatic activity.\",\n      \"method\": \"Endogenous protein co-purification from placenta, functional Ca2+ uptake in Xenopus oocytes with pharmacological inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — endogenous complex identified and functional effect shown in oocytes with mechanistic inhibitor, single lab\",\n      \"pmids\": [\"18445599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The annexin 2–S100A10 complex association with TRPV6 is regulated by the cAMP/PKA/calcineurin A (CnA) pathway; forskolin-stimulated PKA activity promotes anx2-S100A10 complex formation, while CnA-dependent dephosphorylation of annexin 2 is required for association with TRPV6 and augments Ca2+ influx in Caco-2 intestinal cells.\",\n      \"method\": \"Co-immunoprecipitation, 45Ca uptake assays, pharmacological inhibition of PKA and CnA in 16HBE14o- and Caco-2 cells\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical and functional data from two cell lines, but single lab\",\n      \"pmids\": [\"18187190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPV6 mediates maternal-fetal Ca2+ transport in mice; TRPV6 knockout fetuses show 40% lower 45Ca transport from mother, lower fetal blood Ca2+, lower ash weight, and lower amniotic Ca2+. TRPV6 mRNA/protein localizes to intraplacental yolk sac and visceral extraplacental yolk sac, co-localizing with calbindin-D9K.\",\n      \"method\": \"Trpv6 knockout mice, 45Ca radiotracer transport assay, immunolocalization, RT-PCR\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with quantitative radiotracer readout and localization data, strong evidence\",\n      \"pmids\": [\"18348695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPV6 is expressed in the apical membrane of epididymal epithelium (not in sperm); mice homozygous for the pore-dead D541A mutation have 10-fold higher Ca2+ in cauda epididymal fluid, 7-8-fold reduced Ca2+ absorption through epididymal epithelium, and severely impaired male fertility with reduced sperm motility and viability despite intact spermatogenesis.\",\n      \"method\": \"Trpv6(D541A/D541A) knock-in mice, Ca2+ measurement of epididymal fluid, Ca2+ absorption assay, fertility testing, immunolocalization\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — channel-dead knock-in with quantitative Ca2+ absorption phenotype; mechanistically links TRPV6 pore function to epididymal Ca2+ homeostasis and male fertility\",\n      \"pmids\": [\"21540454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PIP2 is a direct activator of TRPV6; intracellular ATP maintains TRPV6 activity indirectly by serving as substrate for type III PI4 kinases to resynthesize PIP2. In excised patches, MgATP-dependent reactivation is blocked by PI4K inhibitors; PIP2 (but not PI4P) activates reconstituted TRPV6 in planar lipid bilayers.\",\n      \"method\": \"Excised inside-out patch clamp, planar lipid bilayer reconstitution of purified TRPV6, pharmacological PI4K inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of purified channel in bilayers plus excised patch pharmacology establishes direct PIP2 activation\",\n      \"pmids\": [\"21810903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In vivo TRPV6 translation initiates at a non-AUG codon (ACG upstream of annotated AUG), producing an N-terminally extended protein 40 residues longer. The extended N-terminus increases plasma membrane trafficking and provides an additional scaffold for channel assembly, while the channel's biophysical properties remain similar to the shorter form.\",\n      \"method\": \"Mass spectrometry of endogenous protein, mutagenesis of initiation codons, cell surface biotinylation, electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — endogenous protein identified by MS, functional trafficking consequence shown by biotinylation and electrophysiology\",\n      \"pmids\": [\"23612980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of rat TRPV6 at 3.25 Å reveals Ca2+ selectivity determined by direct coordination by a ring of aspartate side chains in the selectivity filter; intracellular domains form an 'intracellular skirt' involved in allosteric modulation; cation-binding sites at the pore axis and extracellular vestibule define the Ca2+ permeation mechanism.\",\n      \"method\": \"X-ray crystallography at 3.25 Å resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution crystal structure with identified ion-binding sites; foundational structural paper\",\n      \"pmids\": [\"27296226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cryo-EM structures of human TRPV6 in open and closed states reveal that channel opening involves an α-to-π helical transition in the pore-lining S6 helix at an alanine hinge below the selectivity filter, causing S6 to bend and rotate (iris-like gating). The selectivity filter adopts similar conformations in both states. PIP2 increases open probability.\",\n      \"method\": \"Cryo-electron microscopy, electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structures of both open and closed states, defining gating mechanism\",\n      \"pmids\": [\"29258289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"2-APB inhibits TRPV6 by binding in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helix bundle and inducing channel closure by modulating protein-lipid interactions; comparison of wild-type and high-affinity Y467A mutant structures defined the binding site.\",\n      \"method\": \"Crystal structures and cryo-EM of TRPV6-2-APB complexes, mutagenesis, functional electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination of inhibitor-bound complex combined with mutagenesis and functional validation\",\n      \"pmids\": [\"29941865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of TRPV6 inactivated by calmodulin (CaM) shows 1:1 stoichiometry (one CaM per TRPV6 tetramer) with CaM lobes in a head-to-tail arrangement; the CaM C-terminal lobe plugs the channel pore by inserting K115 into a tetra-tryptophan cage at the intracellular entrance via a cation-π interaction.\",\n      \"method\": \"Cryo-electron microscopy, functional electrophysiology\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution inactivated-state structure revealing unique plugging mechanism\",\n      \"pmids\": [\"30116787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nedd4-2 ubiquitinates TRPV6 and reduces its protein abundance and Ca2+ influx primarily via proteasomal (not lysosomal) degradation without significantly altering internalization rate; WW1/WW2 domains of Nedd4-2 interact with TRPV6 termini and serve as a molecular switch limiting ubiquitination by the HECT domain.\",\n      \"method\": \"Xenopus oocyte expression, ubiquitination assays, proteasome/lysosome inhibitors, co-immunoprecipitation, Ca2+ uptake assays, WW domain mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical ubiquitination assay, mechanistic domain mutagenesis, and functional Ca2+ uptake with multiple inhibitors\",\n      \"pmids\": [\"20843805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRPV6 mediates Ca2+ entry in LNCaP prostate cancer cells; TRPV6-mediated Ca2+ uptake activates the NFAT transcription factor downstream; TRPV6 knockdown reduces proliferation rate, S-phase accumulation, and PCNA expression, and decreases apoptosis resistance.\",\n      \"method\": \"siRNA knockdown, Ca2+ imaging, cell cycle analysis, PCNA western blot, NFAT reporter assay in LNCaP cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple defined cellular phenotypes and downstream signaling readout\",\n      \"pmids\": [\"17533368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPV6 translocates to the plasma membrane in prostate cancer cells via an Orai1/TRPC1-mediated Ca2+/Annexin I/S100A11 pathway; TRPV6-overexpressing tumors show enhanced proliferation and apoptosis resistance in xenograft and bone metastasis models.\",\n      \"method\": \"Co-immunoprecipitation, calcium imaging, cell surface biotinylation, siRNA knockdown, xenograft mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway defined by co-IP and functional assays, in vivo confirmation, but mechanistic detail of trafficking remains partially inferred\",\n      \"pmids\": [\"25172921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SGK1 and PKB/Akt increase TRPV6 activity and plasma membrane abundance in Xenopus oocytes; PIKfyve (phosphorylated by SGK1 at S318) further augments TRPV6 activity and membrane expression when co-expressed with active SGK1, identifying a SGK1-PIKfyve axis regulating TRPV6 surface expression.\",\n      \"method\": \"Xenopus oocyte electrophysiology, immunohistochemistry, western blotting with constitutively active kinase mutants\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional electrophysiology with kinase mutants, membrane abundance confirmed, single lab\",\n      \"pmids\": [\"20041238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CaSR activation in the basolateral membrane of intestinal epithelium directly attenuates TRPV6-dependent Ca2+ absorption via a phospholipase C-dependent mechanism; cinacalcet inhibits Ca2+ flux through TRPV6 when co-expressed with CaSR in Xenopus oocytes, and this effect is absent in Trpv6(D541A) mice.\",\n      \"method\": \"Ussing chamber Ca2+ flux assays, Trpv6D541A mice, Xenopus oocyte co-expression, PLC inhibitor (U73122)\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model combined with oocyte co-expression and pharmacological pathway dissection\",\n      \"pmids\": [\"31013259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nipsnap1 associates with TRPV6 (identified by bioinformatics and pull-down) and abolishes TRPV6 currents in electrophysiological recordings without affecting TRPV6 plasma membrane expression, suggesting direct gating inhibition at the membrane.\",\n      \"method\": \"Bioinformatics, GST pull-down, electrophysiology, cell surface biotinylation in HEK293 cells\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional electrophysiology with biotinylation ruling out trafficking, but interaction not confirmed by co-IP\",\n      \"pmids\": [\"18392847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PTP1B interacts with TRPV6 in vivo (bimolecular fluorescence complementation, co-immunoprecipitation); Src kinase phosphorylates TRPV6 tyrosine residues which are dephosphorylated by PTP1B; inhibition of tyrosine phosphatases with DMHV increases TRPV6-mediated Ca2+ entry following store depletion, and this effect is abolished by Src inhibition.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, Ca2+ imaging, phosphatase and kinase inhibitors in HEK293 cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo interaction confirmed by two methods, functional phosphorylation consequence shown, single lab\",\n      \"pmids\": [\"15894168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Numb1 interacts with TRPV6 via TRPV6 C-terminal D716 and Numb1 R434; Numb1 overexpression decreases cytosolic Ca2+ in TRPV6-transfected HEK293 cells; Numb1 mutant lacking TRPV6-binding capacity fails to inhibit TRPV6 activity; Numb knockdown in MCF-7 cells increases TRPV6 expression, Ca2+ influx, and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, FRET, site-directed mutagenesis, Ca2+ imaging, siRNA knockdown in HEK293 and MCF-7 cells\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction mapped to specific residues with FRET confirmation, functional consequence by mutagenesis and siRNA\",\n      \"pmids\": [\"23140583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPV6 is constitutively active in epididymal principal cells and is functionally coupled to TMEM16A (a Ca2+-activated Cl- channel); Ca2+ entry through TRPV6-like channels drives Ca2+-activated chloride conductance; removal of extracellular Ca2+ or La3+ block attenuates both conductances; both proteins co-localize at the apical membrane.\",\n      \"method\": \"Patch clamp on isolated rat cauda epididymal principal cells, pharmacology, in vivo tubule perfusion, co-localization by immunofluorescence, RT-PCR\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology in native cells with pharmacological dissection and in vivo Ca2+ flux, functional coupling established\",\n      \"pmids\": [\"27481714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV6 mediates constitutive Ca2+ influx in epithelial cells and maintains cellular quiescence by activating PP2A, which suppresses IGF-mediated Akt-Tor and Erk signaling; genetic deletion or pharmacological block of Trpv6 causes epithelial cells to re-enter the cell cycle in zebrafish; reintroduction of channel-competent but not channel-dead Trpv6 restores quiescence.\",\n      \"method\": \"Trpv6 genetic knockout in zebrafish, pharmacological blockade, Ca2+ imaging, PP2A activity assay, IGF signaling western blot, human colon carcinoma cell validation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological loss-of-function with channel-dead rescue, mechanistic pathway (PP2A→IGF signaling) identified in vivo and in vitro\",\n      \"pmids\": [\"31526479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPV6 activation is autoinhibited by intramolecular interactions: the S4-S5 linker interacts with the C-terminal TRP helix (Arg470:Trp593) and the N-terminal pre-S1 helix interacts with the TRP helix (Trp321:Ile597); PIP2 binds three cationic residues in S5 or C-terminus to disrupt both interactions and activate the channel. Disruption of either interaction by mutation or blocking peptides activates TRPV6.\",\n      \"method\": \"Site-directed mutagenesis, blocking peptides, electrophysiology, molecular modeling\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis and peptide competition with functional electrophysiological readout, single lab\",\n      \"pmids\": [\"32829285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPV6 is required for alcohol-induced intestinal Ca2+ influx, tight junction disruption, and gut barrier dysfunction; ethanol and acetaldehyde directly activate TRPV6 ionic currents; photoaffinity labeling identifies a histidine in TRPV6 as a potential alcohol-binding site; substitution of this histidine and a nearby arginine reduces ethanol-activated currents; Trpv6-/- mice are resistant to alcohol-induced barrier dysfunction.\",\n      \"method\": \"Patch clamp in Caco-2 cells, intestinal organoids, Trpv6-/- mice, photoaffinity labeling (3-azibutanol), site-directed mutagenesis, TEER assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identification of binding site by photoaffinity labeling plus mutagenesis, in vivo genetic confirmation, multiple orthogonal approaches\",\n      \"pmids\": [\"35705057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPV6 promotes breast cancer metastasis by activating NFATC2 through increased phosphorylation of NFATC2IP at Ser204 (with CDK5 as a candidate kinase), leading to NFATC2-driven upregulation of ADAMTS6 and enhanced cell migration.\",\n      \"method\": \"TRPV6 overexpression/knockdown, phospho-western blot, siRNA, NFATC2 reporter, migration assays in breast cancer cells\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway mechanistically defined with multiple molecular readouts, but CDK5 involvement inferred, single lab\",\n      \"pmids\": [\"34265397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maternal TRPV6 in trophoblasts of the fetal labyrinth and yolk sac mediates Ca2+ uptake required for embryonic bone development; Trpv6 deficiency in the mother reduces Ca2+ content in placenta and embryo, causes smaller embryos with shorter, less calcified femurs, and impaired cortical bone microarchitecture persisting to adulthood; re-expression of channel-competent TRPV6 rescues the phenotype.\",\n      \"method\": \"Trpv6 knockout mice, embryo Ca2+ content measurement, trophoblast Ca2+ uptake assay, micro-CT, histomorphometry, immunolocalization\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo maternal-specific loss-of-function with quantitative Ca2+ uptake and bone phenotype, channel-competence rescue\",\n      \"pmids\": [\"30786075\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPV6 is a constitutively active, highly Ca2+-selective tetrameric ion channel that mediates apical Ca2+ entry in epithelial tissues (intestine, kidney, placenta, epididymis); its selectivity filter is formed by a ring of aspartate residues, its gating involves an α-to-π helical transition in S6 at an alanine hinge, and its activity is tightly regulated by: (1) Ca2+-dependent CaM binding that plugs the pore intracellularly via a cation-π interaction, (2) PIP2, which relieves autoinhibitory S4-S5 linker/TRP-helix interactions to activate the channel, (3) ubiquitination by Nedd4-2 promoting proteasomal degradation, (4) trafficking to the plasma membrane via Rab11a and the S100A10-annexin 2 complex (which requires the C-terminal VATTV motif), (5) allosteric modulation by RGS2, Nipsnap1, cyclophilin B, Numb1, and PTP1B/Src, and (6) transcriptional upregulation by 1,25-dihydroxyvitamin D3; downstream of Ca2+ entry, TRPV6 activates NFAT signaling to control cell proliferation and, via PP2A, suppresses IGF-Akt-Tor/Erk signaling to maintain epithelial quiescence.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRPV6 is a constitutively active, highly Ca²⁺-selective tetrameric channel that mediates apical Ca²⁺ entry in absorptive epithelia of the intestine, kidney, placenta, and epididymis, linking transcellular calcium transport to systemic mineral homeostasis, male fertility, and fetal skeletal development. Its selectivity filter is formed by a ring of aspartate residues coordinating Ca²⁺ ions, and channel gating involves an α-to-π helical transition at an alanine hinge in S6; Ca²⁺-dependent inactivation is mediated by calmodulin, which binds 1:1 per tetramer and plugs the intracellular pore entrance via a cation–π interaction, and by PIP₂ hydrolysis, whereas PIP₂ binding activates the channel by disrupting autoinhibitory S4-S5 linker/TRP-helix interactions [PMID:27296226, PMID:29258289, PMID:30116787, PMID:18390907, PMID:32829285]. Channel surface expression is controlled by Rab11a-dependent trafficking, the S100A10–annexin 2 complex (requiring the C-terminal VATTV motif), and Nedd4-2-mediated ubiquitination targeting TRPV6 for proteasomal degradation, while gating is further modulated by RGS2, Nipsnap1, cyclophilin B, Numb1, and Src/PTP1B-dependent tyrosine phosphorylation [PMID:12660155, PMID:16354700, PMID:20843805, PMID:16895908]. Downstream of Ca²⁺ entry, TRPV6 activates NFAT signaling to promote cell proliferation and, via PP2A, suppresses IGF–Akt–Erk signaling to maintain epithelial quiescence; loss of TRPV6 function in vivo impairs maternal–fetal Ca²⁺ transport and bone mineralization, disrupts epididymal Ca²⁺ reabsorption causing male infertility, and confers resistance to alcohol-induced gut barrier dysfunction [PMID:17533368, PMID:31526479, PMID:18348695, PMID:21540454, PMID:35705057].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing the oligomeric state: TRPV6 was shown to assemble as a homotetramer (and heterotetramerize with TRPV5), resolving the stoichiometry of the functional channel and demonstrating that subunit composition tunes inactivation and selectivity properties.\",\n      \"evidence\": \"Sucrose-gradient sedimentation, concatemeric pore-mutant electrophysiology, and co-IP in Xenopus oocytes/HEK293 cells\",\n      \"pmids\": [\"12574114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure yet; inter-subunit interfaces undefined\", \"Physiological relevance of TRPV5/V6 heteromers in native tissues not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying a trafficking mechanism: the S100A10–annexin 2 complex was found to bind TRPV6's C-terminal VATTV motif (critical residue T600) and was required for plasma membrane delivery and channel activity, establishing the first defined route for TRPV6 surface expression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, site-directed mutagenesis (T600A), siRNA knockdown, electrophysiology\",\n      \"pmids\": [\"12660155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The vesicular compartment where S100A10–annexin 2 engages TRPV6 was not identified\", \"Whether the VATTV motif is sufficient for trafficking in native epithelia was not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defining calmodulin as a Ca²⁺-dependent regulator: CaM was shown to bind TRPV6 at N- and C-terminal motifs in a Ca²⁺-dependent manner, and Ca²⁺-insensitive CaM mutants reduced channel currents, establishing CaM as a direct modulator — though whether it acts as activator or inactivator was not yet resolved at the structural level.\",\n      \"evidence\": \"GST pull-down, co-IP, CaM mutant overexpression, electrophysiology in HEK293 cells\",\n      \"pmids\": [\"15123711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CaM–TRPV6 interaction and stoichiometry unknown at this stage\", \"Relative contributions of N- vs. C-terminal CaM binding sites not dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying tyrosine phosphorylation as a regulatory switch: Src was shown to phosphorylate TRPV6, and PTP1B to dephosphorylate it, with net phosphorylation increasing Ca²⁺ entry — establishing a kinase/phosphatase cycle modulating channel activity.\",\n      \"evidence\": \"BiFC, co-IP, Ca²⁺ imaging with Src and phosphatase inhibitors in HEK293 cells\",\n      \"pmids\": [\"15894168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific tyrosine residue(s) phosphorylated were not identified\", \"In vivo relevance of Src/PTP1B regulation not demonstrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying Rab11a as a direct trafficking partner: Rab11a was shown to bind TRPV6's C-terminus and drive its apical membrane delivery, with dominant-negative Rab11a reducing surface expression and Ca²⁺ uptake — placing TRPV6 in the Rab11a recycling endosome pathway.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, surface biotinylation, Ca²⁺ uptake with dominant-negative Rab11a\",\n      \"pmids\": [\"16354700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab11a acts on TRPV6 via direct cargo binding or an adaptor intermediate was not fully resolved\", \"Relationship between Rab11a and S100A10–annexin 2 trafficking routes not clarified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovering GPCR-independent gating modulation by RGS2: RGS2 was found to bind the TRPV6 N-terminus and inhibit currents without reducing surface expression, identifying a non-canonical, G-protein-independent role for an RGS protein as a direct channel gating modulator.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, surface biotinylation, electrophysiology in HEK293 cells\",\n      \"pmids\": [\"16895908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RGS2 N-terminal domain alters gating conformations unknown\", \"Physiological stimulus controlling RGS2–TRPV6 interaction not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linking TRPV6 Ca²⁺ entry to proliferative signaling: TRPV6 knockdown in prostate cancer cells reduced NFAT activation, cell proliferation, and apoptosis resistance, establishing that TRPV6-mediated Ca²⁺ influx drives a Ca²⁺–NFAT signaling axis controlling cell cycle progression.\",\n      \"evidence\": \"siRNA knockdown, NFAT reporter assay, cell cycle analysis, Ca²⁺ imaging in LNCaP cells\",\n      \"pmids\": [\"17533368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which NFAT isoform is the primary effector was not defined\", \"Whether TRPV6-NFAT signaling occurs in normal epithelia or is cancer-specific was unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing PIP₂ as a direct channel activator and its hydrolysis as an inactivation mechanism: PIP₂ dialysis prevented Ca²⁺-dependent inactivation, PIP₂ depletion by inducible phosphatase inhibited TRPV6, and Ca²⁺ influx itself drove PIP₂ hydrolysis via PLC, revealing a negative feedback loop.\",\n      \"evidence\": \"Patch clamp, inducible 5-phosphatase, PIP₂ dialysis, wortmannin, fura-2 imaging\",\n      \"pmids\": [\"18390907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PIP₂ binding site on TRPV6 not yet mapped\", \"Relative contribution of PIP₂ depletion vs. CaM binding to inactivation not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating TRPV6's physiological role in maternal–fetal Ca²⁺ transport: Trpv6 knockout fetuses showed 40% reduced placental ⁴⁵Ca transport, lower blood Ca²⁺, and reduced mineralization, establishing TRPV6 as the rate-limiting apical entry step for transplacental calcium delivery.\",\n      \"evidence\": \"Trpv6 knockout mice, ⁴⁵Ca radiotracer transport, immunolocalization in yolk sac/placenta\",\n      \"pmids\": [\"18348695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether compensatory mechanisms partially sustain Ca²⁺ transport in knockouts was not dissected\", \"The vitamin D-dependent transcriptional regulation of placental TRPV6 was not assessed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying Nedd4-2-mediated ubiquitination as a degradation pathway: Nedd4-2 was shown to ubiquitinate TRPV6 and target it for proteasomal (not lysosomal) degradation, with WW domains acting as a molecular switch — establishing ubiquitin-dependent protein turnover as a key mechanism limiting TRPV6 abundance.\",\n      \"evidence\": \"Ubiquitination assays, proteasome/lysosome inhibitors, WW domain mutagenesis, Ca²⁺ uptake in Xenopus oocytes\",\n      \"pmids\": [\"20843805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitinated lysine residues on TRPV6 not mapped\", \"Physiological signals triggering Nedd4-2 engagement not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Proving TRPV6 pore function is essential for epididymal Ca²⁺ absorption and male fertility: Trpv6(D541A) knock-in mice had massively elevated epididymal fluid Ca²⁺ and severely impaired sperm motility and fertility, directly linking the channel's ion-conducting pore to a specific physiological outcome.\",\n      \"evidence\": \"Channel-dead D541A knock-in mice, epididymal fluid Ca²⁺ measurement, Ca²⁺ absorption assay, fertility testing\",\n      \"pmids\": [\"21540454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRPV6 has non-conducting roles in epididymal cells was not tested\", \"Downstream Ca²⁺-dependent effectors in epididymal epithelium not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating direct PIP₂ activation in a reconstituted system: purified TRPV6 in planar lipid bilayers was activated by PIP₂ but not PI4P, and MgATP-dependent reactivation required PI4K activity, proving that PIP₂ is a direct, sufficient lipid activator rather than acting through an intermediate.\",\n      \"evidence\": \"Purified TRPV6 reconstituted in planar lipid bilayers, excised patch clamp, PI4K inhibitors\",\n      \"pmids\": [\"21810903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PIP₂ binding site still not structurally defined\", \"Lipid species specificity beyond PIP₂/PI4P not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solving the atomic structure: the crystal structure of TRPV6 at 3.25 Å revealed how aspartate side chains in the selectivity filter directly coordinate Ca²⁺ ions, defined the intracellular 'skirt' domain architecture, and identified cation-binding sites along the permeation pathway — providing the structural framework for understanding selectivity and gating.\",\n      \"evidence\": \"X-ray crystallography at 3.25 Å resolution (rat TRPV6)\",\n      \"pmids\": [\"27296226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only a single conformational state captured\", \"PIP₂ and CaM binding sites not visualized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the gating mechanism: cryo-EM structures in open and closed states revealed that gating proceeds through an α-to-π helical transition at an alanine hinge in S6, causing iris-like rotation — a novel gating mechanism for TRP channels.\",\n      \"evidence\": \"Cryo-EM of human TRPV6 in open/closed states, electrophysiology\",\n      \"pmids\": [\"29258289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate gating states not captured\", \"How PIP₂ binding allosterically triggers the S6 transition not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing the CaM-mediated inactivation mechanism at atomic resolution: cryo-EM showed that one CaM binds per TRPV6 tetramer in a head-to-tail arrangement and directly plugs the pore by inserting CaM K115 into a tetra-tryptophan cage via cation–π interaction — a unique channel inactivation mechanism.\",\n      \"evidence\": \"Cryo-EM of CaM-bound TRPV6, electrophysiology\",\n      \"pmids\": [\"30116787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CaM initially docks to the channel before pore insertion is unknown\", \"Whether CaM-mediated inactivation and PIP₂ depletion are cooperative or independent processes not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural basis of pharmacological inhibition: 2-APB was shown to bind in the S1–S4 bundle cytoplasmic pocket, modulating protein–lipid interactions to close the channel — providing a template for structure-based drug design targeting TRPV6.\",\n      \"evidence\": \"Crystal structures and cryo-EM of TRPV6–2-APB complexes, Y467A mutagenesis, electrophysiology\",\n      \"pmids\": [\"29941865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the 2-APB site overlaps with endogenous modulators not tested\", \"Selectivity of 2-APB for TRPV6 over other TRP channels not structurally explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing TRPV6 as a quiescence signal via PP2A: constitutive Ca²⁺ influx through TRPV6 was shown to activate PP2A, which suppresses IGF–Akt–Erk signaling to maintain epithelial quiescence in zebrafish, with channel-dead rescue failing to restore quiescence — revealing that TRPV6's growth-suppressive role is ion-conductance-dependent.\",\n      \"evidence\": \"Trpv6 knockout zebrafish, pharmacological blockade, channel-dead rescue, PP2A activity assay, IGF pathway western blots, human colon carcinoma validation\",\n      \"pmids\": [\"31526479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ca²⁺ activates PP2A downstream of TRPV6 is mechanistically undefined\", \"Whether the quiescence function is conserved across all TRPV6-expressing mammalian epithelia not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining a basolateral-to-apical feedback loop: CaSR activation on the basolateral membrane was shown to attenuate apical TRPV6-mediated Ca²⁺ absorption via PLC-dependent PIP₂ depletion, with confirmation in Trpv6(D541A) mice — integrating PIP₂ regulation with systemic Ca²⁺-sensing physiology.\",\n      \"evidence\": \"Ussing chamber assays, Trpv6D541A mice, CaSR/TRPV6 co-expression in oocytes, PLC inhibitor\",\n      \"pmids\": [\"31013259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CaSR-TRPV6 coupling occurs in tissues beyond intestine not tested\", \"Quantitative contribution of PIP₂ depletion vs. other PLC products (DAG, IP₃) not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the PIP₂-dependent autoinhibition mechanism: specific intramolecular contacts (S4-S5 linker:TRP helix, pre-S1:TRP helix) were shown to hold TRPV6 in an autoinhibited state, with PIP₂ disrupting these interactions to activate the channel — providing a molecular model for how PIP₂ allosterically gates TRPV6.\",\n      \"evidence\": \"Site-directed mutagenesis, blocking peptides, electrophysiology, molecular modeling\",\n      \"pmids\": [\"32829285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct structural visualization of PIP₂ in the binding site\", \"Blocking peptide approach requires validation with purified components\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovering ethanol as a direct TRPV6 activator: ethanol and acetaldehyde were shown to activate TRPV6 currents, and photoaffinity labeling identified a histidine as part of the alcohol-binding site; Trpv6⁻/⁻ mice were resistant to alcohol-induced gut barrier dysfunction — establishing TRPV6 as a molecular mediator of alcohol-induced epithelial injury.\",\n      \"evidence\": \"Patch clamp, photoaffinity labeling, site-directed mutagenesis, Trpv6⁻/⁻ mice, TEER assay, intestinal organoids\",\n      \"pmids\": [\"35705057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete alcohol-binding pocket not structurally resolved\", \"Whether alcohol-induced TRPV6 activation contributes to Ca²⁺ malabsorption in alcoholism not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the complete structural basis of PIP₂ binding and how it allosterically couples to the S6 gating transition; the mechanism by which TRPV6-dependent Ca²⁺ activates PP2A; whether the NFAT-driven proliferative and PP2A-driven quiescence programs are cell-type-specific or co-exist; and the full spectrum of post-translational modifications (phosphorylation sites, glycosylation) regulating TRPV6 in native epithelia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PIP₂ binding site not structurally resolved on TRPV6\", \"Ca²⁺-to-PP2A coupling mechanism unknown\", \"Integration of NFAT and PP2A signaling arms not addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 5, 10, 11, 13, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 11, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 10, 12, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [18, 26, 29]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [9, 10, 11, 13, 14, 28]}\n    ],\n    \"complexes\": [\n      \"TRPV6 homotetramer\",\n      \"TRPV5/TRPV6 heterotetramer\"\n    ],\n    \"partners\": [\n      \"TRPV5\",\n      \"ANXA2\",\n      \"S100A10\",\n      \"RAB11A\",\n      \"CALM1\",\n      \"RGS2\",\n      \"NEDD4L\",\n      \"NUMB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}