Affinage

TRPV6

Transient receptor potential cation channel subfamily V member 6 · UniProt Q9H1D0

Length
765 aa
Mass
87.3 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2003 High

    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

    PMID:12574114

    Open questions at the time
    • No high-resolution structure yet; inter-subunit interfaces undefined
    • Physiological relevance of TRPV5/V6 heteromers in native tissues not established
  2. 2003 High

    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

    PMID:12660155

    Open questions at the time
    • 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
  3. 2004 High

    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

    PMID:15123711

    Open questions at the time
    • Structural basis of CaM–TRPV6 interaction and stoichiometry unknown at this stage
    • Relative contributions of N- vs. C-terminal CaM binding sites not dissected
  4. 2004 Medium

    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

    PMID:15894168

    Open questions at the time
    • Specific tyrosine residue(s) phosphorylated were not identified
    • In vivo relevance of Src/PTP1B regulation not demonstrated
  5. 2006 High

    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

    PMID:16354700

    Open questions at the time
    • 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
  6. 2006 High

    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

    PMID:16895908

    Open questions at the time
    • Mechanism by which RGS2 N-terminal domain alters gating conformations unknown
    • Physiological stimulus controlling RGS2–TRPV6 interaction not identified
  7. 2007 High

    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

    PMID:17533368

    Open questions at the time
    • Which NFAT isoform is the primary effector was not defined
    • Whether TRPV6-NFAT signaling occurs in normal epithelia or is cancer-specific was unclear
  8. 2008 High

    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

    PMID:18390907

    Open questions at the time
    • PIP₂ binding site on TRPV6 not yet mapped
    • Relative contribution of PIP₂ depletion vs. CaM binding to inactivation not quantified
  9. 2008 High

    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

    PMID:18348695

    Open questions at the time
    • Whether compensatory mechanisms partially sustain Ca²⁺ transport in knockouts was not dissected
    • The vitamin D-dependent transcriptional regulation of placental TRPV6 was not assessed
  10. 2010 High

    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

    PMID:20843805

    Open questions at the time
    • Specific ubiquitinated lysine residues on TRPV6 not mapped
    • Physiological signals triggering Nedd4-2 engagement not identified
  11. 2011 High

    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

    PMID:21540454

    Open questions at the time
    • Whether TRPV6 has non-conducting roles in epididymal cells was not tested
    • Downstream Ca²⁺-dependent effectors in epididymal epithelium not identified
  12. 2011 High

    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

    PMID:21810903

    Open questions at the time
    • PIP₂ binding site still not structurally defined
    • Lipid species specificity beyond PIP₂/PI4P not tested
  13. 2016 High

    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)

    PMID:27296226

    Open questions at the time
    • Only a single conformational state captured
    • PIP₂ and CaM binding sites not visualized
  14. 2017 High

    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

    PMID:29258289

    Open questions at the time
    • Intermediate gating states not captured
    • How PIP₂ binding allosterically triggers the S6 transition not resolved at atomic level
  15. 2018 High

    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

    PMID:30116787

    Open questions at the time
    • 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
  16. 2018 High

    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

    PMID:29941865

    Open questions at the time
    • Whether the 2-APB site overlaps with endogenous modulators not tested
    • Selectivity of 2-APB for TRPV6 over other TRP channels not structurally explained
  17. 2019 High

    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

    PMID:31526479

    Open questions at the time
    • How Ca²⁺ activates PP2A downstream of TRPV6 is mechanistically undefined
    • Whether the quiescence function is conserved across all TRPV6-expressing mammalian epithelia not demonstrated
  18. 2019 High

    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

    PMID:31013259

    Open questions at the time
    • Whether CaSR-TRPV6 coupling occurs in tissues beyond intestine not tested
    • Quantitative contribution of PIP₂ depletion vs. other PLC products (DAG, IP₃) not dissected
  19. 2020 Medium

    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

    PMID:32829285

    Open questions at the time
    • No direct structural visualization of PIP₂ in the binding site
    • Blocking peptide approach requires validation with purified components
  20. 2022 High

    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

    PMID:35705057

    Open questions at the time
    • Complete alcohol-binding pocket not structurally resolved
    • Whether alcohol-induced TRPV6 activation contributes to Ca²⁺ malabsorption in alcoholism not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-382551 Transport of small molecules 6
Partners
ANXA2CALM1NEDD4LNUMBRAB11ARGS2S100A10TRPV5
Complex memberships
TRPV5/TRPV6 heterotetramerTRPV6 homotetramer

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Sucrose-gradient sedimentation, electrophysiology of concatemeric channels with pore mutant, co-immunoprecipitation from Xenopus oocytes, HEK293 functional assays The EMBO journal High 12574114
2003 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. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, whole-cell electrophysiology, immunohistochemistry The EMBO journal High 12660155
2004 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. GST pull-down, co-immunoprecipitation, overexpression of Ca2+-insensitive CaM mutants, chimeric TRPV6/TRPV5 electrophysiology in HEK293 cells The Journal of biological chemistry High 15123711
2006 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. Yeast two-hybrid, co-immunoprecipitation, cell surface biotinylation, Ca2+ uptake assays, dominant-negative Rab11a coexpression Molecular and cellular biology High 16354700
2006 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. Yeast two-hybrid, GST pull-down, cell surface biotinylation, whole-cell electrophysiology in HEK293 cells The Journal of biological chemistry High 16895908
2008 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. Whole-cell patch clamp, excised patch recording, inducible phosphatase system, PIP2 dialysis, wortmannin pharmacology, fura-2 Ca2+ imaging The Journal of biological chemistry High 18390907
2008 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. Ca2+-influx measurements in transfected HEK293 cells treated with klotho, beta-glucuronidase, and endoglycosidase-F Nephrology, dialysis, transplantation Medium 18495742
2008 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. Endogenous protein co-purification from placenta, functional Ca2+ uptake in Xenopus oocytes with pharmacological inhibition The Journal of biological chemistry Medium 18445599
2008 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. Co-immunoprecipitation, 45Ca uptake assays, pharmacological inhibition of PKA and CnA in 16HBE14o- and Caco-2 cells Cell calcium Medium 18187190
2008 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. Trpv6 knockout mice, 45Ca radiotracer transport assay, immunolocalization, RT-PCR Journal of bone and mineral research High 18348695
2011 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. Trpv6(D541A/D541A) knock-in mice, Ca2+ measurement of epididymal fluid, Ca2+ absorption assay, fertility testing, immunolocalization Science signaling High 21540454
2011 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. Excised inside-out patch clamp, planar lipid bilayer reconstitution of purified TRPV6, pharmacological PI4K inhibition FASEB journal High 21810903
2013 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. Mass spectrometry of endogenous protein, mutagenesis of initiation codons, cell surface biotinylation, electrophysiology The Journal of biological chemistry High 23612980
2016 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. X-ray crystallography at 3.25 Å resolution Nature High 27296226
2017 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. Cryo-electron microscopy, electrophysiology Nature High 29258289
2018 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. Crystal structures and cryo-EM of TRPV6-2-APB complexes, mutagenesis, functional electrophysiology Nature communications High 29941865
2018 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. Cryo-electron microscopy, functional electrophysiology Science advances High 30116787
2010 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. Xenopus oocyte expression, ubiquitination assays, proteasome/lysosome inhibitors, co-immunoprecipitation, Ca2+ uptake assays, WW domain mutagenesis The Journal of biological chemistry High 20843805
2007 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. siRNA knockdown, Ca2+ imaging, cell cycle analysis, PCNA western blot, NFAT reporter assay in LNCaP cells Oncogene High 17533368
2014 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. Co-immunoprecipitation, calcium imaging, cell surface biotinylation, siRNA knockdown, xenograft mouse models Proceedings of the National Academy of Sciences of the United States of America Medium 25172921
2009 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. Xenopus oocyte electrophysiology, immunohistochemistry, western blotting with constitutively active kinase mutants The Journal of membrane biology Medium 20041238
2019 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. Ussing chamber Ca2+ flux assays, Trpv6D541A mice, Xenopus oocyte co-expression, PLC inhibitor (U73122) JCI insight High 31013259
2008 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. Bioinformatics, GST pull-down, electrophysiology, cell surface biotinylation in HEK293 cells Pflugers Archiv : European journal of physiology Medium 18392847
2004 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. Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, Ca2+ imaging, phosphatase and kinase inhibitors in HEK293 cells Cellular signalling Medium 15894168
2012 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. Co-immunoprecipitation, FRET, site-directed mutagenesis, Ca2+ imaging, siRNA knockdown in HEK293 and MCF-7 cells Cell calcium Medium 23140583
2016 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. Patch clamp on isolated rat cauda epididymal principal cells, pharmacology, in vivo tubule perfusion, co-localization by immunofluorescence, RT-PCR The Journal of general physiology Medium 27481714
2019 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. Trpv6 genetic knockout in zebrafish, pharmacological blockade, Ca2+ imaging, PP2A activity assay, IGF signaling western blot, human colon carcinoma cell validation eLife High 31526479
2020 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. Site-directed mutagenesis, blocking peptides, electrophysiology, molecular modeling iScience Medium 32829285
2022 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. Patch clamp in Caco-2 cells, intestinal organoids, Trpv6-/- mice, photoaffinity labeling (3-azibutanol), site-directed mutagenesis, TEER assay Cell reports High 35705057
2021 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. TRPV6 overexpression/knockdown, phospho-western blot, siRNA, NFATC2 reporter, migration assays in breast cancer cells Cancer letters Medium 34265397
2019 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. Trpv6 knockout mice, embryo Ca2+ content measurement, trophoblast Ca2+ uptake assay, micro-CT, histomorphometry, immunolocalization Journal of bone and mineral research High 30786075

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 AtMKK1 mediates ABA-induced CAT1 expression and H2O2 production via AtMPK6-coupled signaling in Arabidopsis. The Plant journal : for cell and molecular biology 258 18248592
2003 Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. The EMBO journal 255 12574114
2003 Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. The EMBO journal 228 12660155
2002 Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Laboratory investigation; a journal of technical methods and pathology 201 12480925
2007 TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways. Oncogene 200 17533368
2016 Crystal structure of the epithelial calcium channel TRPV6. Nature 184 27296226
2017 Opening of the human epithelial calcium channel TRPV6. Nature 164 29258289
2000 Human calcium transport protein CaT1. Biochemical and biophysical research communications 162 11097838
2003 The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell calcium 155 12765695
2008 The role of TRPV6 in breast carcinogenesis. Molecular cancer therapeutics 151 18245667
2003 Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney. Journal of the American Society of Nephrology : JASN 151 14569082
2003 Vitamin D receptor (VDR) knockout mice reveal VDR-independent regulation of intestinal calcium absorption and ECaC2 and calbindin D9k mRNA. The Journal of nutrition 139 12566470
2004 Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)-sensor calmodulin. The Journal of biological chemistry 103 15123711
2012 Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor-negative breast cancer. Molecular cancer therapeutics 100 22807578
2014 TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival. Proceedings of the National Academy of Sciences of the United States of America 96 25172921
2006 Direct interaction with Rab11a targets the epithelial Ca2+ channels TRPV5 and TRPV6 to the plasma membrane. Molecular and cellular biology 95 16354700
2018 Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. Nature communications 94 29941865
2020 Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. Gastroenterology 93 31930989
2005 TRPV5 and TRPV6 in Ca(2+) (re)absorption: regulating Ca(2+) entry at the gate. Pflugers Archiv : European journal of physiology 93 16044309
2011 Male fertility depends on Ca²+ absorption by TRPV6 in epididymal epithelia. Science signaling 91 21540454
2012 The role of the TRPV6 channel in cancer. The Journal of physiology 89 22331416
2008 The beta-glucuronidase klotho exclusively activates the epithelial Ca2+ channels TRPV5 and TRPV6. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 89 18495742
2018 Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6. Science advances 86 30116787
2008 Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 86 18348695
2010 Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone 85 20399919
2001 1,25-Dihydroxyvitamin D3 increases the expression of the CaT1 epithelial calcium channel in the Caco-2 human intestinal cell line. BMC physiology 85 11545681
1992 Control of peroxisome proliferation in Saccharomyces cerevisiae by ADR1, SNF1 (CAT1, CCR1) and SNF4 (CAT3). Yeast (Chichester, England) 83 1355328
2005 TRPV6 potentiates calcium-dependent cell proliferation. Cell calcium 77 16356545
2007 Uterine TRPV6 expression during the estrous cycle and pregnancy in a mouse model. American journal of physiology. Endocrinology and metabolism 75 17374692
2002 Store depletion-activated CaT1 currents in rat basophilic leukemia mast cells are inhibited by 2-aminoethoxydiphenyl borate. Evidence for a regulatory component that controls activation of both CaT1 and CRAC (Ca(2+) release-activated Ca(2+) channel) channels. The Journal of biological chemistry 73 12011062
2001 Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics 73 11549322
2005 The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease. Naunyn-Schmiedeberg's archives of pharmacology 70 15747113
2020 TRPV6 as A Target for Cancer Therapy. Journal of Cancer 67 31897233
2011 Alternative perspective on intestinal calcium absorption: proposed complementary actions of Ca(v)1.3 and TRPV6. Nutrition reviews 67 21729089
2008 Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels. The Journal of biological chemistry 67 18390907
2013 The in vivo TRPV6 protein starts at a non-AUG triplet, decoded as methionine, upstream of canonical initiation at AUG. The Journal of biological chemistry 64 23612980
2016 TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6. Biochimica et biophysica acta. Molecular cell research 63 27913205
2018 TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism. American journal of human genetics 61 29861107
2010 Heavy metal cations permeate the TRPV6 epithelial cation channel. Cell calcium 61 21146870
2016 Lidocaine inhibits the invasion and migration of TRPV6-expressing cancer cells by TRPV6 downregulation. Oncology letters 60 27446413
2011 Protein kinase C-dependent ubiquitination and clathrin-mediated endocytosis of the cationic amino acid transporter CAT-1. The Journal of biological chemistry 60 21212261
2003 The TRPV6 gene, cDNA and protein. Cell calcium 60 12765696
2012 Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1). Journal of molecular and cellular cardiology 58 22705145
2004 Ca2+ dependence of the Ca2+-selective TRPV6 channel. The Journal of biological chemistry 57 15184369
2013 Human TRPV5 and TRPV6: key players in cadmium and zinc toxicity. Cell calcium 55 23968883
2003 (Patho)physiological implications of the novel epithelial Ca2+ channels TRPV5 and TRPV6. Pflugers Archiv : European journal of physiology 55 12748856
2011 Intracellular ATP supports TRPV6 activity via lipid kinases and the generation of PtdIns(4,5) P₂. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 51 21810903
2008 Expression of calcium channel TRPV6 in ovine epithelial tissue. Veterinary journal (London, England : 1997) 51 18701326
2022 Calcium selective channel TRPV6: Structure, function, and implications in health and disease. Gene 48 35031425
2006 Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6. American journal of physiology. Renal physiology 48 16705151
2003 Store-operated Ca2+ current and TRPV6 channels in lymph node prostate cancer cells. The Journal of biological chemistry 48 14534305
2010 Chemical inhibitors of the calcium entry channel TRPV6. Pharmaceutical research 46 21057859
2009 Tamoxifen inhibits TRPV6 activity via estrogen receptor-independent pathways in TRPV6-expressing MCF-7 breast cancer cells. Molecular cancer research : MCR 46 19996302
2009 Dynamic expression of calcium-regulatory molecules, TRPV6 and S100G, in the uterine endometrium during pregnancy in pigs. Biology of reproduction 45 19641180
2008 ATF-1 transcription factor regulates the expression of ccg-1 and cat-1 genes in response to fludioxonil under OS-2 MAP kinase in Neurospora crassa. Fungal genetics and biology : FG & B 44 18948219
2007 Concerted action of associated proteins in the regulation of TRPV5 and TRPV6. Biochemical Society transactions 43 17233615
2005 L-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes. Blood 43 16210335
2004 Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1alpha,25-dihydroxy Vitamin D3 and dietary Ca2+. The Journal of steroid biochemistry and molecular biology 43 15225790
2019 Activation of the calcium sensing receptor attenuates TRPV6-dependent intestinal calcium absorption. JCI insight 42 31013259
2011 Coexpression and estrogen-mediated regulation of TRPV6 and PMCA1 in the human endometrium during the menstrual cycle. Molecular reproduction and development 42 21400627
2014 Knockout of TRPV6 causes osteopenia in mice by increasing osteoclastic differentiation and activity. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 41 24686448
2019 CAT1/SLC7A1 acts as a cellular receptor for bovine leukemia virus infection. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 31648581
2021 Calcium channel TRPV6 promotes breast cancer metastasis by NFATC2IP. Cancer letters 39 34265397
2018 TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton. American journal of medical genetics. Part A 39 30144375
2014 TRPV6 channels. Handbook of experimental pharmacology 39 24756713
2006 RGS2 inhibits the epithelial Ca2+ channel TRPV6. The Journal of biological chemistry 39 16895908
1992 Differential response of maize catalases to abscisic acid: Vp1 transcriptional activator is not required for abscisic acid-regulated Cat1 expression. Proceedings of the National Academy of Sciences of the United States of America 38 1388272
2008 The annexin 2-S100A10 complex and its association with TRPV6 is regulated by cAMP/PKA/CnA in airway and gut epithelia. Cell calcium 37 18187190
2008 Parallel selection on TRPV6 in human populations. PloS one 37 18301763
2008 The human TRPV6 channel protein is associated with cyclophilin B in human placenta. The Journal of biological chemistry 37 18445599
2009 Endogenous expression of TRPV5 and TRPV6 calcium channels in human leukemia K562 cells. American journal of physiology. Cell physiology 35 19295174
1998 Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines. The Journal of biological chemistry 35 9614060
2010 Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2. The Journal of biological chemistry 33 20843805
2009 Regulation of the Ca(2+) channel TRPV6 by the kinases SGK1, PKB/Akt, and PIKfyve. The Journal of membrane biology 33 20041238
2008 The Tsc/Rheb signaling pathway controls basic amino acid uptake via the Cat1 permease in fission yeast. Molecular genetics and genomics : MGG 33 18219492
2022 TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response. Cell reports 32 35705057
2012 The transient receptor potential channel TRPV6 is dynamically expressed in bone cells but is not crucial for bone mineralization in mice. Journal of cellular physiology 32 21732366
2005 1,25-Dihydroxyvitamin D and 25-hydroxyvitamin D--mediated regulation of TRPV6 (a putative epithelial calcium channel) mRNA expression in Caco-2 cells. European journal of nutrition 32 16362534
2021 Colorectal Cancer-Derived CAT1-Positive Extracellular Vesicles Alter Nitric Oxide Metabolism in Endothelial Cells and Promote Angiogenesis. Molecular cancer research : MCR 31 33579815
2020 The calcium channel TRPV6 is a novel regulator of RANKL-induced osteoclastic differentiation and bone absorption activity through the IGF-PI3K-AKT pathway. Cell proliferation 28 33159483
2016 TRPV6 plays a new role in predicting survival of patients with esophageal squamous cell carcinoma. Diagnostic pathology 28 26818094
2020 Autoinhibition of TRPV6 Channel and Regulation by PIP2. iScience 27 32829285
2014 Fission yeast arrestin-related trafficking adaptor, Arn1/Any1, is ubiquitinated by Pub1 E3 ligase and regulates endocytosis of Cat1 amino acid transporter. Biology open 27 24876389
2020 TRPV6 calcium channel directs homeostasis of the mammary epithelial sheets and controls epithelial mesenchymal transition. Scientific reports 26 32895467
2020 Trichostatin A Induces Autophagy in Cervical Cancer Cells by Regulating the PRMT5-STC1-TRPV6-JNK Pathway. Pharmacology 26 33142290
2005 Catecholamines' enhancement of inducible nitric oxide synthase-induced nitric oxide biosynthesis involves CAT-1 and CAT-2A. Anesthesia and analgesia 26 15976236
2008 Identification of Nipsnap1 as a novel auxiliary protein inhibiting TRPV6 activity. Pflugers Archiv : European journal of physiology 25 18392847
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2020 Natural product inspired optimization of a selective TRPV6 calcium channel inhibitor. RSC medicinal chemistry 24 33479695
2018 Δ9-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6. Pharmacological research 24 30170189
2016 Coupling of TRPV6 and TMEM16A in epithelial principal cells of the rat epididymis. The Journal of general physiology 24 27481714
2013 Expression of TRPV6 and CaBP-D28k in the egg shell gland (uterus) during the oviposition cycle of the laying hen. British poultry science 24 23796121
2011 Acceleration of keratinocyte differentiation by transient receptor potential vanilloid (TRPV6) channel activation. Journal of the European Academy of Dermatology and Venereology : JEADV 24 21175869
1998 Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin. Amino acids 24 9891757
2020 Antitumor effects of novel mAbs against cationic amino acid transporter 1 (CAT1) on human CRC with amplified CAT1 gene. Cancer science 23 33211385
2019 Maternal Transient Receptor Potential Vanilloid 6 (Trpv6) Is Involved In Offspring Bone Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 22 30786075
2012 Regulation of calcium influx and signaling pathway in cancer cells via TRPV6-Numb1 interaction. Cell calcium 22 23140583
2009 Arginine transport in human erythroid cells: discrimination of CAT1 and 4F2hc/y+LAT2 roles. Pflugers Archiv : European journal of physiology 22 19562367
2019 Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6. eLife 21 31526479
2004 Tyrosine phosphatase PTP1B interacts with TRPV6 in vivo and plays a role in TRPV6-mediated calcium influx in HEK293 cells. Cellular signalling 20 15894168