Affinage

TRPV5

Transient receptor potential cation channel subfamily V member 5 · UniProt Q9NQA5

Length
729 aa
Mass
82.6 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPV5 is a highly Ca2+-selective, homotetrameric TRP channel that serves as the rate-limiting apical entry gate for active transcellular Ca2+ reabsorption, established genetically by knockout mice that show severe renal Ca2+ wasting, compensatory intestinal hyperabsorption, and bone thinning (PMID:14679186), and by a zebrafish loss-of-function ortholog causing lethal ossification defects (PMID:21670068). Beyond the kidney, TRPV5 resides in the osteoclast ruffled border where its Ca2+ transport is essential for bone resorption (PMID:16291808). The channel assembles via reciprocal N- and C-tail interactions into 400 kDa tetramers that can co-assemble with TRPV6 to generate channels of distinct permeation properties (PMID:12574114, PMID:15489237), with the outer pore organized around a pore helix and an Asp542 selectivity-filter high-affinity Ca2+ site (PMID:14630907) and an intracellular W583 gate (PMID:28374795). Channel gating is governed structurally by PI(4,5)P2, which binds at the N-linker/S4-S5/S6 interface to open the lower gate, and by Ca2+-loaded calmodulin, whose C-lobe Lys116 engages Trp583 to drive Ca2+-dependent inactivation (PMID:30305626, PMID:30975749); protons sensed extracellularly at Glu522 and intracellularly via pore-helix rotation close the channel, and low pH inhibits by precluding PI(4,5)P2 binding (PMID:14525991, PMID:16121193, PMID:35476976). Surface abundance and activity are set by a regulatory network: Klotho hydrolyzes TRPV5 N-glycans to entrap the channel through galectin lattices (PMID:16239475, PMID:18606998), FGF23 acts through the FGFR-αKlotho complex via an ERK1/2-SGK1-WNK4 cascade (PMID:24434184), PTH-PKA phosphorylates Thr709 to relieve inhibitory calmodulin binding (PMID:19423690, PMID:21576356), PKC phosphorylation of Ser299/Ser654 blocks caveolin-1-dependent endocytosis (PMID:18305097, PMID:17006539), and NDPK-B phosphorylates His711 to activate the channel (PMID:24523290). Trafficking and stability are further tuned by the S100A10-annexin-2 complex required for plasma membrane delivery (PMID:12660155), constitutive clathrin- and caveolae-mediated endocytosis with Rab11a-dependent recycling (PMID:18077461), and calbindin-D28K, which buffers peri-pore Ca2+ to prevent inactivation and sustain high transport rates (PMID:16763551). A recurrent kidney-stone-associated L530R variant abolishes Ca2+ transport by disrupting TM5 packing near the selectivity filter (PMID:28847730).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 Medium

    Established that the TRPV5 C-terminal tail encodes the determinants of Ca2+-dependent inactivation, localizing feedback regulation to a defined cytoplasmic region.

    Evidence C-terminal truncation mutagenesis with patch-clamp in HEK293 cells

    PMID:12634930

    Open questions at the time
    • Did not identify the molecular partner mediating inactivation
    • Mapped regions but not specific residues or interacting Ca2+ sensor
  2. 2003 High

    Defined the channel as a tetramer and resolved outer-pore architecture, answering how TRPV5 achieves Ca2+ selectivity and how subunit composition diversifies channel behavior.

    Evidence Sucrose gradient/IP and concatemeric electrophysiology for tetramer assembly; SCAM pore mapping; knockout micropuncture for in vivo function

    PMID:12574114 PMID:14630907 PMID:14679186

    Open questions at the time
    • Atomic structure not yet available
    • Heterotetramer stoichiometry in native tissue unresolved
  3. 2003 High

    Identified S100A10-annexin-2 as a trafficking chaperone required to route TRPV5 to the plasma membrane via its C-terminal VATTV motif, clarifying how the channel reaches its functional site.

    Evidence Yeast two-hybrid, GST pulldown, co-IP, mutagenesis (T599), siRNA, electrophysiology

    PMID:12660155

    Open questions at the time
    • Mechanism of vesicular routing downstream of S100A10 not detailed
    • Did not address regulated vs constitutive delivery
  4. 2003 High

    Localized extracellular pH sensing to Glu522, defining how luminal acidification gates the channel.

    Evidence Single-channel patch-clamp, mutagenesis, MTS cysteine accessibility

    PMID:14525991

    Open questions at the time
    • Did not connect extracellular sensor to intracellular conformational changes (resolved later)
  5. 2004 High

    Showed reciprocal N- and C-tail interactions drive tetrameric assembly and surface trafficking, explaining the dominant-negative effect of tail deletions.

    Evidence GST pulldown, co-IP, mutagenesis, oocyte 45Ca2+ uptake and patch-clamp

    PMID:15489237

    Open questions at the time
    • Structural basis of tail-tail contacts not resolved
    • Did not address regulation of assembly
  6. 2004 Medium

    Identified accessory Ca2+ sensors and kinase/scaffold inputs (80K-H, SGK1/3-NHERF2) modulating activity and surface targeting, broadening the regulatory network.

    Evidence Co-IP, 45Ca2+ binding/uptake, EF-hand and PDZ deletion mutagenesis, oocyte electrophysiology

    PMID:15100231 PMID:15319523 PMID:15665527

    Open questions at the time
    • Single-lab interactions without in vivo confirmation
    • Physiological hierarchy among regulators unclear
  7. 2005 High

    Revealed Klotho as a glycosidase that traps TRPV5 at the surface by hydrolyzing N-glycans, providing a hormone-independent mechanism to sustain Ca2+ entry.

    Evidence Enzymatic assay, Ca2+ influx, surface expression in HEK293; osteoclast KO; PIP2 electrophysiology

    PMID:16230466 PMID:16239475 PMID:16291808

    Open questions at the time
    • Initial enzymatic identity (glucuronidase vs sialidase) later refined
    • Did not resolve glycan-lattice partner at this stage
  8. 2006 Medium

    Established calbindin-D28K as a peri-channel Ca2+ buffer preventing inactivation, and identified additional modulators (BSPRY, FKBP52) plus a pH-driven vesicular surface-recruitment mechanism.

    Evidence TIRF microscopy, binding/fractionation, 45Ca2+ uptake, electrophysiology, PPIase mutagenesis

    PMID:16352746 PMID:16380433 PMID:16763551 PMID:17178838

    Open questions at the time
    • Relative contribution of buffering vs structural inactivation control unquantified
    • Modulator interactions mostly single-lab
  9. 2008 High

    Distinguished endocytic routes and their hormonal control, showing PKC phosphorylation of Ser299/Ser654 inhibits caveolin-1-mediated retrieval while WNK4 promotes it, tuning surface abundance.

    Evidence Dominant-negative dynamin, caveolin-1/clathrin siRNA and KO rescue, mutagenesis, biotinylation, electrophysiology

    PMID:17006539 PMID:18077461 PMID:18305097 PMID:20061383

    Open questions at the time
    • In vivo significance of caveolar vs clathrin routes not fully separated
    • WNK4 mechanism outside kinase domain undefined
  10. 2009 High

    Defined PTH dual action: PKA phosphorylation of Thr709 raising open probability and CaR-coupled PKC stimulation, linking systemic calcium-regulating signals to channel gating and trafficking.

    Evidence FRET cAMP/Ca2+, biotinylation, PKA application, mutagenesis, patch-clamp, CaR dominant-negative

    PMID:19157541 PMID:19423690

    Open questions at the time
    • T709 phosphorylation mechanism on CaM binding not yet structurally defined (resolved 2011)
    • CaR coupling single-lab
  11. 2011 High

    Resolved the calmodulin-TRPV5 interaction and stoichiometry and showed PKA-Thr709 phosphorylation enhances activity by displacing inhibitory CaM, unifying gating and hormonal control.

    Evidence NMR spectroscopy, mutagenesis (W702A, R706E), patch-clamp; zebrafish ossification genetics

    PMID:21576356 PMID:21670068

    Open questions at the time
    • Full-channel structural context of CaM binding not yet available (resolved by cryo-EM)
  12. 2013 Medium

    Expanded surface regulation to disease-relevant extracellular factors (UMOD, MUC1) and degradation (UBR4), and refined the Klotho glycan/galectin mechanism toward galectin-3.

    Evidence Co-IP, siRNA, caveolin-1 KO rescue, N-glycan mutants, in vivo Umod-/- and Klotho colitis models, glycan analysis

    PMID:23466996 PMID:23747339 PMID:23970553 PMID:27036738

    Open questions at the time
    • Galectin-1 vs galectin-3 identity in DCT remained debated across studies
    • UBR4 ubiquitination sites unmapped
  13. 2014 High

    Separated Klotho's hormonal (FGF23-FGFR-αKlotho-ERK1/2-SGK1-WNK4) and enzymatic trafficking roles, and identified NDPK-B/PHPT1 histidine phosphorylation of His711 as a distinct activation switch.

    Evidence FGF23/αKlotho KO mice, pathway inhibition; inside-out patch, NDPK-B shRNA/KO mice, H711 mutagenesis; trafficking dissection

    PMID:24434184 PMID:24523290 PMID:25378396

    Open questions at the time
    • Integration of multiple Klotho mechanisms in vivo incomplete
    • Histidine-phosphorylation dynamics in tissue unquantified
  14. 2018 High

    Provided atomic structures showing how PI(4,5)P2 opens the lower gate, how calmodulin's Lys116 engages Trp583 for Ca2+-dependent inhibition, and how inhibitors occlude the pore, giving a structural basis for gating.

    Evidence Cryo-EM of full-length TRPV5 with PI(4,5)P2, CaM, and econazole; MD simulations; W583 mutagenesis

    PMID:28374795 PMID:29323279 PMID:30305626

    Open questions at the time
    • Dynamic transitions between states inferred not directly captured at first
    • Native-membrane lipid composition effects unaddressed
  15. 2019 High

    Captured CaM-binding stoichiometric flexibility in nanodiscs and used structure-guided screening to find new inhibitor sites, advancing both mechanism and pharmacology.

    Evidence Cryo-EM in lipid nanodiscs, W583A mutant, virtual screening with electrophysiology

    PMID:30975749 PMID:31647410

    Open questions at the time
    • Therapeutic selectivity over TRPV6 not established
    • Functional consequence of variable CaM stoichiometry in vivo unknown
  16. 2022 High

    Unified gating modulators structurally, showing low pH inhibits by precluding PI(4,5)P2 activation and that PKA acts by preventing CaM-mediated inactivation rather than directly opening the gate.

    Evidence Cryo-EM across multiple pH and modulator conditions capturing intermediate states

    PMID:35476976

    Open questions at the time
    • Kinetics of state transitions in living cells not resolved
    • Coupling between His711/Thr709 phosphorylation and structural states untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many converging regulatory inputs (glycan trapping, hormonal kinases, lipid and pH gating, calmodulin, accessory chaperones) are integrated and prioritized within a single native distal-tubule cell to set Ca2+ reabsorption set-points remains unresolved.
  • No quantitative model integrating trafficking and gating regulators in vivo
  • Tissue-specific stoichiometry of TRPV5 heteromers (TRPV6, TRPML3) unknown
  • Human disease genetics beyond a single variant largely uncharacterized in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 4 R-HSA-5653656 Vesicle-mediated transport 4
Partners
CALBINDIN-D28KCALMODULINFKBP52KLOTHOMUC1NHERF2S100A10UBR4
Complex memberships
S100A10-annexin 2 complexTRPV5 homotetramerTRPV5-calmodulin complexTRPV5/TRPV6 heterotetramer

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Klotho, acting as a beta-glucuronidase, hydrolyzes extracellular N-linked oligosaccharides on TRPV5, entrapping the channel in the plasma membrane and sustaining calcium channel activity at the cell surface. Biochemical enzymatic assay, Ca2+ influx measurements, cell surface expression studies in HEK293 cells Science High 16239475
2008 Klotho removes terminal alpha2,6-linked sialic acids from TRPV5 N-glycan chains, exposing galactose-N-acetylglucosamine that binds galectin-1, which forms a lattice retaining TRPV5 at the plasma membrane. Knockdown of ST6Gal-1 prevents this regulation. RNAi knockdown of ST6Gal-1, glycan analysis, Ca2+ influx measurements, co-expression in cell lines lacking endogenous ST6Gal-1 with rescue by recombinant ST6Gal-1 Proceedings of the National Academy of Sciences of the United States of America High 18606998
2003 TRPV5-knockout mice exhibit severely diminished active Ca2+ reabsorption in the early distal convoluted tubule (confirmed by in vivo micropuncture), severe hypercalciuria despite elevated vitamin D, compensatory intestinal Ca2+ hyperabsorption, and reduced trabecular and cortical bone thickness, establishing TRPV5 as the essential luminal entry gate for active Ca2+ reabsorption in the kidney. Germline knockout mouse model, in vivo micropuncture, urinary and serum Ca2+ measurements, bone histomorphometry The Journal of clinical investigation High 14679186
2003 TRPV5 and TRPV6 assemble as homotetramers (400 kDa complexes) and can form heterotetramers; different heterotetrameric compositions produce Ca2+ channels with distinct Ca2+-dependent inactivation, Ba2+ selectivity, and pharmacological properties. Sucrose gradient sedimentation, immunoprecipitation, electrophysiology of concatemeric channels with pore mutants in HEK293 cells The EMBO journal High 12574114
2003 S100A10 directly binds the conserved C-terminal VATTV sequence of TRPV5 (critical residue T599) and forms a heterotetrameric complex with annexin 2; this S100A10-annexin 2 complex is required to route TRPV5 to the plasma membrane. Annexin 2 siRNA knockdown abolishes TRPV5-mediated currents. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, electrophysiology The EMBO journal High 12660155
2014 FGF23 promotes renal Ca2+ reabsorption and apical membrane abundance of TRPV5 in distal tubules through binding the FGF receptor-αKlotho complex and activating an ERK1/2-SGK1-WNK4 signaling cascade, not through αKlotho's glycosidase activity. Fgf23 and αKlotho knockout mice, immunolocalization, signaling pathway inhibition, renal Ca2+ balance measurements The EMBO journal High 24434184
2018 Cryo-EM structures of TRPV5 with PI(4,5)P2 reveal a binding site between the N-linker, S4-S5 linker and S6 helix; PI(4,5)P2 binding induces conformational rearrangements in the lower gate that open the channel. Cryo-EM with calmodulin shows two TRPV5 C-terminal peptides anchoring one CaM molecule, with Lys116 on CaM C-lobe forming a cation-π interaction with Trp583 at the intracellular gate to mediate Ca2+-dependent inhibition. Cryo-electron microscopy, molecular dynamics simulations Nature communications High 30305626
2018 Cryo-EM structure of full-length rabbit TRPV5 in complex with econazole reveals the inhibitor occupies a hydrophobic pocket analogous to the phosphatidylinositide/vanilloid-binding site in TRPV1; the econazole-bound structure adopts a closed conformation with a distinct lower gate that occludes Ca2+ permeation. Cryo-electron microscopy, molecular dynamics simulations Nature structural & molecular biology High 29323279
2009 PTH activates TRPV5 via the cAMP-PKA pathway by phosphorylating threonine-709 on TRPV5, increasing channel open probability without altering surface expression. Alanine substitution of T709 abolishes both in vitro phosphorylation and PTH-mediated TRPV5 stimulation. FRET-based cAMP and Ca2+ dynamics, cell-surface biotinylation, PKA catalytic subunit application, site-directed mutagenesis, patch-clamp electrophysiology Journal of the American Society of Nephrology High 19423690
2005 PIP2 activates TRPV5 by a mechanism independent of Mg2+ binding to the selectivity filter and reduces TRPV5 sensitivity to Mg2+-induced slow conformational channel closure. Mutation of aspartate-542 (critical Mg2+-binding site in selectivity filter) abolishes Mg2+-induced slow inhibition; PLC activation sensitizes TRPV5 to this Mg2+-induced slow inhibition by hydrolyzing PIP2. Whole-cell patch-clamp, site-directed mutagenesis, intracellular perfusion with PIP2 or receptor-mediated PLC activation The Journal of general physiology High 16230466
2005 TRPV5 is localized to the ruffled border membrane of osteoclasts; TRPV5 knockout osteoclasts show increased number and size but nearly absent bone resorption in pit assays, establishing TRPV5-mediated Ca2+ transport as essential for osteoclastic bone resorption. Immunostaining, TRPV5 knockout mouse analysis, in vitro bone marrow osteoclast cultures, resorption pit assays Proceedings of the National Academy of Sciences of the United States of America High 16291808
2006 Calbindin-D28K translocates to the plasma membrane at low intracellular Ca2+ and directly associates with TRPV5, where it buffers Ca2+ entering through the channel in close proximity to the pore, preventing Ca2+-dependent channel inactivation and facilitating high transcellular Ca2+ transport rates. Protein-binding analysis, subcellular fractionation, evanescent-field (TIRF) microscopy, 45Ca2+ uptake, electrophysiology, transcellular Ca2+ transport assays in primary tubule cells infected with lentivirus The EMBO journal High 16763551
2008 TRPV5 undergoes constitutive caveolae-mediated (caveolin-1-dependent, clathrin-independent) endocytosis. PKC activators increase TRPV5 cell-surface abundance by inhibiting this endocytosis via phosphorylation of Ser-299 and Ser-654 on TRPV5. PTH also increases TRPV5 surface abundance through this PKC-caveolin pathway. Dominant-negative dynamin, siRNA knockdown of caveolin-1 and clathrin, caveolin-1 knockout cells with rescue, site-directed mutagenesis, whole-cell patch-clamp, cell-surface biotinylation American journal of physiology. Renal physiology High 18305097
2006 Tissue kallikrein (TK) stimulates Ca2+ reabsorption via bradykinin receptor type 2 activation of the PLC/DAG/PKC pathway, which phosphorylates TRPV5 at Ser-299 and Ser-654, increasing TRPV5 plasma membrane abundance by delaying its retrieval. Primary renal epithelial cell cultures, PKC pharmacology, BK receptor antagonism, cell-surface labeling, mutagenesis of PKC sites (S299A, S654A) The EMBO journal High 17006539
2004 The intracellular N-tail (residues 64–77) and C-tail (residues 596–601) of TRPV5 mediate homotetrameric assembly via N-N, C-C, and N-C interactions; deletion of either tail alone causes dominant-negative suppression by preventing plasma membrane trafficking of the channel complex. GST pulldown, co-immunoprecipitation, site-directed mutagenesis, patch-clamp, 45Ca2+ uptake in oocytes The Journal of biological chemistry High 15489237
2003 Extracellular acidification inhibits TRPV5 with pKa ~6.55; glutamate-522 in the extracellular loop between TM5 and TM6 is the extracellular pH sensor. E522Q mutation decreases pH sensitivity and abolishes proton-mediated reduction of open probability without altering single-channel conductance block component. Whole-cell and single-channel patch-clamp, site-directed mutagenesis, methanethiosulfonate (MTS) cysteine accessibility The Journal of biological chemistry High 14525991
2005 Intracellular acidification causes clockwise rotation of the TRPV5 pore helix (detected by substituted cysteine accessibility method), which facilitates closure of the selectivity filter gate by extracellular protons; internal and external pH sensors cross-regulate each other via this pore helix conformational change. Substituted cysteine accessibility method (SCAM), whole-cell patch-clamp, site-directed mutagenesis The EMBO journal High 16121193
2011 Calmodulin binds Ca2+-dependently to a C-terminal fragment (residues 696–729) of TRPV5 in a 1 CaM:2 TRPV5 C-terminus stoichiometry; TRPV5 mutations W702A and R706E abolish CaM binding and strongly reduce Ca2+-dependent channel inactivation. PTH-induced PKA phosphorylation of T709 diminishes CaM binding to TRPV5, thereby enhancing channel open probability. NMR spectroscopy, site-directed mutagenesis, patch-clamp electrophysiology Molecular and cellular biology High 21576356
2007 TRPV5 is constitutively internalized via dynamin- and clathrin-dependent endocytosis; internalized channels traffic to Rab11a-positive perinuclear recycling endosomes and can return to the cell surface. The recycling kinetics are decreased by intracellular Ca2+ chelation (BAPTA-AM), indicating Ca2+-controlled recycling. Dynamin dominant-negative, clathrin siRNA, Rab11a co-localization, brefeldin A block, fluorescence microscopy, electrophysiology The Journal of biological chemistry High 18077461
2009 Activation of the Ca2+-sensing receptor (CaR) co-localized with TRPV5 at the luminal membrane of distal tubule stimulates TRPV5-mediated Ca2+ influx via PMA-insensitive PKC isoforms acting on Ser-299 and Ser-654 of TRPV5; dominant-negative CaR(R185Q) and S299A/S654A TRPV5 mutations abolish this effect. Patch-clamp electrophysiology, Fura-2 Ca2+ imaging, site-directed mutagenesis, dominant-negative CaR construct Cell calcium Medium 19157541
2004 80K-H directly interacts with TRPV5, co-localizes in kidney, and acts as a Ca2+ sensor that modulates TRPV5 activity via its EF-hand structures, glutamic stretch, and HDEL sequence; inactivation of the EF-hands reduces TRPV5-mediated Ca2+ current and increases TRPV5 sensitivity to intracellular Ca2+, accelerating feedback inhibition. cDNA microarray identification, co-immunoprecipitation, 45Ca2+ binding assays, site-directed mutagenesis of EF-hands, patch-clamp electrophysiology The Journal of biological chemistry Medium 15100231
2006 Extracellular alkalinization rapidly recruits a pool of TRPV5-containing vesicles to the cell surface via a 'kiss and linger' vesicular mechanism without full membrane fusion, increasing functional TRPV5 channel activity; extracellular acidification reverses this, retrieving vesicles from the surface. Total internal reflection fluorescence (TIRF) microscopy, cell surface protein labeling, electrophysiology, 45Ca2+ uptake, functional channel recovery after chemobleaching Molecular and cellular biology Medium 17178838
2008 Klotho (beta-glucuronidase) selectively activates TRPV5 and TRPV6 but not TRPV4 or TRPM6 among renal ion channels, indicating channel-type specificity of the glycan-hydrolysis mechanism. Ca2+ influx measurements in HEK293 cells expressing different renal channels, endoglycosidase-F deglycosylation control Nephrology, dialysis, transplantation Medium 18495742
2014 NDPK-B (histidine kinase) activates TRPV5 channel activity and Ca2+ flux through phosphorylation of histidine-711 in the TRPV5 C-terminal tail; the histidine phosphatase PHPT1 reverses this activation. NDPK-B knockdown decreases TRPV5 activity, and NDPK-B knockout mice show increased urinary Ca2+ excretion on high-Ca2+ diet. Inside-out patch-clamp, NDPK-B shRNA knockdown, NDPK-B knockout mice urinary Ca2+ measurements, site-directed mutagenesis of H711 Molecular biology of the cell High 24523290
2013 Uromodulin (UMOD) upregulates TRPV5 cell-surface abundance by acting extracellularly to impair caveolin-1-mediated endocytosis; UMOD has no effect in caveolin-1-null cells or with N-glycan-deficient TRPV5; disease mutant UMOD with reduced secretion fails to increase TRPV5 activity. Immunofluorescence shows reduced TRPV5 expression in Umod-/- mouse kidneys. Whole-cell patch-clamp, cell-surface biotinylation, siRNA knockdown, caveolin-1 knockout cells with rescue, immunofluorescence in Umod-/- mice Kidney international High 23466996
2005 FKBP52 physically interacts specifically with TRPV5 and co-localizes in the distal nephron; it inhibits TRPV5-mediated Ca2+ influx through its peptidyl-prolyl cis-trans isomerase (PPIase) domain, as PPIase domain mutation abolishes the inhibitory effect. Co-immunoprecipitation, 45Ca2+ uptake, patch-clamp electrophysiology, siRNA knockdown, FK-506 pharmacology, PPIase domain mutagenesis American journal of physiology. Renal physiology Medium 16352746
2006 BSPRY interacts with TRPV5 (confirmed by GST pulldown and co-IP), co-localizes in mouse kidney, and reduces TRPV5-mediated Ca2+ influx without altering channel surface abundance, indicating direct modulation of channel activity. GST pulldown, co-immunoprecipitation, 45Ca2+ uptake in MDCK-TRPV5 cells, immunostaining Journal of the American Society of Nephrology Medium 16380433
2008 WNK4 decreases TRPV5 cell-surface abundance by stimulating caveolae-mediated endocytosis via a region outside its kinase domain; this WNK4-dependent tonic inhibition lowers basal TRPV5 levels and thereby amplifies the dynamic range of PKC- and PTH-mediated stimulation of TRPV5. Deletion analysis of WNK4 domains, patch-clamp electrophysiology, cell-surface biotinylation, PKC activator co-stimulation experiments The Journal of biological chemistry Medium 20061383
2008 WNK3 positively regulates TRPV5 plasma membrane expression via a kinase-dependent mechanism (kinase-inactive D294A mutation abolishes effect); WNK3 promotes complex glycosylation and exocytosis of TRPV5 via microtubule-dependent secretory pathway, as colchicine blocks this effect. Xenopus oocyte 45Ca2+ uptake, voltage-clamp electrophysiology, kinase-inactive mutagenesis, colchicine treatment, glycosylation analysis American journal of physiology. Renal physiology Medium 18768590
2004 SGK1 and SGK3 (but not SGK2) together with scaffold protein NHERF2 stimulate TRPV5-mediated Ca2+ entry in Xenopus oocytes; the second PDZ domain of NHERF2 is required for stabilization/targeting of TRPV5 to the plasma membrane, and TRPV5 C-tail interacts with NHERF2 in a Ca2+-independent manner. Xenopus oocyte 45Ca2+ uptake, voltage-clamp, NHERF2 PDZ deletion mutants, GST pulldown, overlay assays, chemiluminescence surface quantification Cellular physiology and biochemistry Medium 15319523 15665527
2006 NHERF4 (PDZK2) interacts with the C-terminus of TRPV5 through its fourth PDZ domain (PDZ1 also contributes); confirmed by yeast two-hybrid, GST pulldown with in vitro translated NHERF4 and oocyte lysates, and co-immunoprecipitation in HEK293 cells. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, PDZ domain deletion analysis Pflugers Archiv Medium 16565876
2002 The C-terminal tail of TRPV5 (ECaC1) mediates Ca2+-dependent channel inactivation; deletion of the last 30 amino acids (G701X) and truncations around residues 649-653 significantly reduce or abolish Ca2+-dependent inactivation, identifying two critical C-terminal domains. Carboxyl-terminal truncation mutagenesis, patch-clamp electrophysiology in HEK293 cells Pflugers Archiv Medium 12634930
2019 High-resolution cryo-EM structures of full-length TRPV5 in lipid nanodiscs, a TRPV5 W583A mutant, and TRPV5 in complex with CaM reveal a flexible stoichiometry of CaM binding and the mechanism of calcium-dependent regulation; W583 at the intracellular gate is critical for CaM-mediated inactivation. Cryo-electron microscopy, lipid nanodisc reconstitution, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 30975749
2022 Cryo-EM shows that low pH inhibits TRPV5 by precluding PI(4,5)P2 binding/activation; intermediate conformations at low pH reveal transition from open to closed state. PI(4,5)P2 is the primary modulator of channel gating; PKA controls TRPV5 by preventing CaM binding and channel inactivation rather than directly opening the gate. Cryo-electron microscopy, structural analysis of multiple pH and modulator conditions Cell reports High 35476976
2017 Tryptophan-583 at the terminus of the intracellular pore forms a gate for Ca2+ permeation through TRPV5; W583 mutants show profoundly enhanced Ca2+ influx and increased cell death; a glycine residue above W583 may act as a flexible hinge to rearrange the tryptophan gate. Site-directed mutagenesis, patch-clamp electrophysiology, biochemical analysis, homology modeling Scientific reports Medium 28374795
2013 Inflammatory cytokines (TNF-α, IFN-γ, IL-1β) induce TRPV5 interaction with E3 ubiquitin ligase UBR4, leading to ubiquitin-dependent TRPV5 degradation; UBR4 siRNA prevents cytokine-induced TRPV5 degradation. Klotho protects TRPV5 from hypersialylation and cytokine-induced endocytosis and degradation in colitis. Co-immunoprecipitation (TRPV5-UBR4), siRNA knockdown of UBR4, adenoviral TRPV5 transduction, transgenic Klotho overexpression mice with colitis model Gastroenterology Medium 23747339
2014 Klotho up-regulates TRPV5 from both inside (as membrane-bound Klotho, mKL, via enhanced forward trafficking blocked by brefeldin A) and outside (as secreted Klotho, sKL, via inhibition of dynamin-dependent endocytosis); both effects require putative sialidase activity of Klotho, and mKL acts via intracellular N-glycosylation-dependent mechanisms. Whole-cell patch-clamp, brefeldin A blockade, dominant-negative dynamin II, sialidase inhibitor, sialidase activity site mutations, cell-surface biotinylation The Journal of biological chemistry Medium 25378396
2013 Klotho increases TRPV5 plasma membrane stability via the TRPV5 N-glycan through a mechanism distinct from sialidase: sialidase activates TRPV5 by inhibiting lipid raft-mediated internalization independently of the N-glycan (N358Q mutant equally activated). Galectin-3 (not galectin-1) is expressed in the distal convoluted tubule, and galectin-3 treatment increases TRPV5-mediated Ca2+ uptake. Biochemical glycan analysis (isoelectric focusing), TIRF microscopy, Ca2+ uptake assays, N-glycosylation mutant analysis, galectin treatment The Journal of biological chemistry Medium 23970553
2016 Mucin-1 (MUC1) increases TRPV5 activity by impairing dynamin-2- and caveolin-1-mediated endocytosis; MUC1 physically interacts with TRPV5 (co-immunoprecipitation), and the MUC1 effect requires N-glycan on TRPV5 and galectin-3 (not galectin-1) binding to VNTR repeats of MUC1, forming a lattice. Patch-clamp electrophysiology, co-immunoprecipitation, dominant-negative dynamin-2, siRNA knockdown of galectins, caveolin-1 analysis, N-glycosylation mutant TRPV5 Journal of the American Society of Nephrology Medium 27036738
2013 TRPML3 associates with TRPV5 to form a novel heteromeric ion channel with distinct pharmacological and biophysical properties compared to TRPML3 or TRPV5 homomers; the heteromeric channel occurs in potentially distinct stoichiometric configurations. Co-immunoprecipitation, single-channel patch-clamp analysis, pharmacological characterization PLoS one Low 23469151
2019 Structure-based virtual screening at the econazole binding site identified novel TRPV5 inhibitors; cryo-EM structures of TRPV5 with these inhibitors revealed novel binding sites distinct from the econazole site, suggesting multiple inhibitory mechanisms. Structure-based virtual screening, cryo-electron microscopy, electrophysiology screening eLife Medium 31647410
2003 Cysteine scanning mutagenesis (SCAM) of the ECaC-TRPV5 outer pore defined three structural domains: a coiled structure (Glu515–Tyr526) connected to a pore helix (~15 amino acids, 527–539) followed by the selectivity filter around Asp542 and a coiled structure before S6. The pore helix is alpha-helical and optimized for cation entry; Asp542 is at the high-Ca2+ affinity site. Substituted cysteine accessibility method (SCAM) with MTSET/MTSES reagents, whole-cell patch-clamp The Journal of biological chemistry Medium 14630907
2011 A loss-of-function mutation in the single zebrafish TRPV5/6 orthologue (trpv5/6) causes lethal severe bone ossification defects with 68% reduced calcium content; ambient high calcium (25 mM) partially rescues the phenotype. The mutant channel expressed in HEK293 cells lacks Ca2+-selective inward transport activity, directly linking epithelial TRPV5/6-mediated Ca2+ uptake to bone formation. Forward genetic screen in zebrafish, HEK293 cell functional expression, calcium content measurements, genetic rescue with ambient Ca2+ FASEB journal High 21670068
2017 L530R variation in TRPV5 (associated with recurrent kidney stones) abolishes Ca2+ uptake activity in Xenopus oocytes, drastically reduces complex glycosylation, and molecular dynamics simulations show disruption of hydrophobic interaction between L530 and L502, damaging TM5 secondary structure and shifting the Ca2+-selective filter residue D542. Xenopus oocyte 45Ca2+ uptake, western blot glycosylation analysis, molecular dynamics simulations, TRPV6 crystal structure-based homology modeling Biochemical and biophysical research communications Medium 28847730

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science (New York, N.Y.) 519 16239475
2008 Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proceedings of the National Academy of Sciences of the United States of America 344 18606998
2003 Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. The Journal of clinical investigation 337 14679186
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
2001 Sustained nitric oxide production in macrophages requires the arginine transporter CAT2. The Journal of biological chemistry 194 11278602
2001 Function and expression of the epithelial Ca(2+) channel family: comparison of mammalian ECaC1 and 2. The Journal of physiology 189 11744752
2014 FGF23 promotes renal calcium reabsorption through the TRPV5 channel. The EMBO journal 166 24434184
2003 The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell calcium 155 12765695
2005 The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption. Proceedings of the National Academy of Sciences of the United States of America 147 16291808
2018 Structural insights on TRPV5 gating by endogenous modulators. Nature communications 135 30305626
2009 Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. Journal of the American Society of Nephrology : JASN 121 19423690
2005 PIP2 activates TRPV5 and releases its inhibition by intracellular Mg2+. The Journal of general physiology 116 16230466
2018 Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM. Nature structural & molecular biology 104 29323279
2002 1,25-dihydroxyvitamin D(3)-independent stimulatory effect of estrogen on the expression of ECaC1 in the kidney. Journal of the American Society of Nephrology : JASN 104 12138142
2000 Molecular cloning, tissue distribution, and chromosomal mapping of the human epithelial Ca2+ channel (ECAC1). Genomics 99 10945469
2006 Calbindin-D28K dynamically controls TRPV5-mediated Ca2+ transport. The EMBO journal 97 16763551
2001 Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1. British journal of pharmacology 97 11588099
2001 Gene structure and regulation of the murine epithelial calcium channels ECaC1 and 2. Biochemical and biophysical research communications 97 11741335
2019 Structural insight into TRPV5 channel function and modulation. Proceedings of the National Academy of Sciences of the United States of America 95 30975749
2005 TRPV5 and TRPV6 in Ca(2+) (re)absorption: regulating Ca(2+) entry at the gate. Pflugers Archiv : European journal of physiology 93 16044309
1999 CAT2-mediated L-arginine transport and nitric oxide production in activated macrophages. The Biochemical journal 93 10333501
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
2003 Mechanism and molecular determinant for regulation of rabbit transient receptor potential type 5 (TRPV5) channel by extracellular pH. The Journal of biological chemistry 86 14525991
2008 Protein kinase C inhibits caveolae-mediated endocytosis of TRPV5. American journal of physiology. Renal physiology 81 18305097
2005 Conformational changes of pore helix coupled to gating of TRPV5 by protons. The EMBO journal 74 16121193
2001 Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics 74 11549322
2011 Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone. Molecular and cellular biology 72 21576356
2004 Molecular determinants in TRPV5 channel assembly. The Journal of biological chemistry 72 15489237
2009 Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5. Cell calcium 71 19157541
2005 The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease. Naunyn-Schmiedeberg's archives of pharmacology 70 15747113
2008 TRPV5: an ingeniously controlled calcium channel. Kidney international 68 18596722
2004 Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 67 15319523
2001 Transgenic tobacco plants expressing the maize Cat2 gene have altered catalase levels that affect plant-pathogen interactions and resistance to oxidative stress. Transgenic research 66 11817543
2016 TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6. Biochimica et biophysica acta. Molecular cell research 64 27913205
2005 Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice. Journal of the American Society of Nephrology : JASN 64 16148038
2014 Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1. Molecular biology of the cell 63 24523290
2013 Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis. Kidney international 61 23466996
2006 Tissue kallikrein stimulates Ca(2+) reabsorption via PKC-dependent plasma membrane accumulation of TRPV5. The EMBO journal 60 17006539
1998 Three murine cataract mutants (Cat2) are defective in different gamma-crystallin genes. Genomics 58 9782080
1987 Translational control of photo-induced expression of the Cat2 catalase gene during leaf development in maize. Proceedings of the National Academy of Sciences of the United States of America 58 3472236
2014 Klotho up-regulates renal calcium channel transient receptor potential vanilloid 5 (TRPV5) by intra- and extracellular N-glycosylation-dependent mechanisms. The Journal of biological chemistry 57 25378396
2011 Trpv5/6 is vital for epithelial calcium uptake and bone formation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 21670068
2006 Extracellular pH dynamically controls cell surface delivery of functional TRPV5 channels. Molecular and cellular biology 57 17178838
2005 Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 57 15665527
2004 80K-H as a new Ca2+ sensor regulating the activity of the epithelial Ca2+ channel transient receptor potential cation channel V5 (TRPV5). The Journal of biological chemistry 57 15100231
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
2019 Structure-based characterization of novel TRPV5 inhibitors. eLife 54 31647410
2005 Vitamin D upregulates expression of ECaC1 mRNA in semicircular canal. Biochemical and biophysical research communications 53 15883024
1987 Isolation and characterization of a cDNA clone for the Cat2 gene in maize and its homology with other catalases. Proceedings of the National Academy of Sciences of the United States of America 51 2821546
2009 Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear. Acta oto-laryngologica 49 19922080
2006 Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6. American journal of physiology. Renal physiology 49 16705151
2002 The carboxyl terminus of the epithelial Ca(2+) channel ECaC1 is involved in Ca(2+)-dependent inactivation. Pflugers Archiv : European journal of physiology 49 12634930
2013 Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Amino acids 44 23864433
2007 Concerted action of associated proteins in the regulation of TRPV5 and TRPV6. Biochemical Society transactions 43 17233615
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
2002 Interleukin-10 inhibition of nitric oxide biosynthesis involves suppression of CAT-2 transcription. Nitric oxide : biology and chemistry 43 11829538
2016 Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients. Journal of the American Society of Nephrology : JASN 42 27036738
2022 Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. Cell reports 41 35476976
2013 The epithelial calcium channel TRPV5 is regulated differentially by klotho and sialidase. The Journal of biological chemistry 41 23970553
2009 TRPV5 gene polymorphisms in renal hypercalciuria. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 39 19131347
2003 Outer pore topology of the ECaC-TRPV5 channel by cysteine scan mutagenesis. The Journal of biological chemistry 39 14630907
2007 TRPV5 is internalized via clathrin-dependent endocytosis to enter a Ca2+-controlled recycling pathway. The Journal of biological chemistry 37 18077461
2011 TRPV5 and TRPV6 in transcellular Ca(2+) transport: regulation, gene duplication, and polymorphisms in African populations. Advances in experimental medicine and biology 36 21290300
2014 Coordinated regulation of TRPV5-mediated Ca²⁺ transport in primary distal convolution cultures. Pflugers Archiv : European journal of physiology 35 24557712
2009 Endogenous expression of TRPV5 and TRPV6 calcium channels in human leukemia K562 cells. American journal of physiology. Cell physiology 35 19295174
2006 Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice. Journal of the American Society of Nephrology : JASN 35 17005931
2005 The immunophilin FKBP52 inhibits the activity of the epithelial Ca2+ channel TRPV5. American journal of physiology. Renal physiology 35 16352746
1994 Anaerobic degradation of catechol by Desulfobacterium sp. strain Cat2 proceeds via carboxylation to protocatechuate. Applied and environmental microbiology 35 7944370
2010 Characterization of calmodulin binding domains in TRPV2 and TRPV5 C-tails. Amino acids 34 20686800
2021 Oxoglaucine mediates Ca2+ influx and activates autophagy to alleviate osteoarthritis through the TRPV5/calmodulin/CAMK-II pathway. British journal of pharmacology 33 33786819
2008 WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway. American journal of physiology. Renal physiology 33 18768590
2002 Epithelial Ca(2+) channel (ECAC1) in autosomal dominant idiopathic hypercalciuria. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 33 12198212
2012 Expression of transient receptor potential vanilloid channels TRPV5 and TRPV6 in human blood lymphocytes and Jurkat leukemia T cells. The Journal of membrane biology 30 23111462
2013 Post-translational loss of renal TRPV5 calcium channel expression, Ca(2+) wasting, and bone loss in experimental colitis. Gastroenterology 29 23747339
2011 Decreased expression of the epithelial Ca2+ channel TRPV5 and TRPV6 in human renal cell carcinoma associated with vitamin D receptor. The Journal of urology 29 22019165
2010 WNK4 kinase stimulates caveola-mediated endocytosis of TRPV5 amplifying the dynamic range of regulation of the channel by protein kinase C. The Journal of biological chemistry 29 20061383
2019 TRPV5 in renal tubular calcium handling and its potential relevance for nephrolithiasis. Kidney international 28 31471161
2008 Bone resorption inhibitor alendronate normalizes the reduced bone thickness of TRPV5(-/-) mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 18597625
1997 Influence of UV-light on the expression of the Cat2 and Cat3 catalase genes in maize. Free radical biology & medicine 28 9214589
2009 Transepithelial calcium transport in prolactin-exposed intestine-like Caco-2 monolayer after combinatorial knockdown of TRPV5, TRPV6 and Ca(v)1.3. The journal of physiological sciences : JPS 27 19885716
2007 Regulation of the epithelial calcium channel TRPV5 by extracellular factors. Current opinion in nephrology and hypertension 27 17565273
2006 Interaction of the epithelial Ca2+ channels TRPV5 and TRPV6 with the intestine- and kidney-enriched PDZ protein NHERF4. Pflugers Archiv : European journal of physiology 27 16565876
2023 Novel flavin-containing monooxygenase protein FMO1 interacts with CAT2 to negatively regulate drought tolerance through ROS homeostasis and ABA signaling pathway in tomato. Horticulture research 26 37101513
2021 Mutual Promotion of LAP2 and CAT2 Synergistically Regulates Plant Salt and Osmotic Stress Tolerance. Frontiers in plant science 25 34177987
2018 Vitamin D receptor suppresses proliferation and metastasis in renal cell carcinoma cell lines via regulating the expression of the epithelial Ca2+ channel TRPV5. PloS one 25 29659618
2017 A Gate Hinge Controls the Epithelial Calcium Channel TRPV5. Scientific reports 25 28374795
2014 TRPV5: a Ca(2+) channel for the fine-tuning of Ca(2+) reabsorption. Handbook of experimental pharmacology 25 24756712
2008 WNK4 regulates the secretory pathway via which TRPV5 is targeted to the plasma membrane. Biochemical and biophysical research communications 25 18703016
2020 Effect of San'ao decoction with scorpio and bombyx batryticatus on CVA mice model via airway inflammation and regulation of TRPA1/TRPV1/TRPV5 channels. Journal of ethnopharmacology 24 32890712
2018 Δ9-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6. Pharmacological research 24 30170189
2006 Identification of BSPRY as a novel auxiliary protein inhibiting TRPV5 activity. Journal of the American Society of Nephrology : JASN 24 16380433
2005 Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages. American journal of physiology. Cell physiology 24 16371438
2007 Rapamycin stimulates arginine influx through CAT2 transporters in human endothelial cells. Biochimica et biophysica acta 23 17397797
2002 Expression of the novel epithelial Ca2+ channel ECaC1 in rat pancreatic islets. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 23 12019295
2007 TRPV5, the gateway to Ca2+ homeostasis. Handbook of experimental pharmacology 22 17217059
2002 Cat2 L-arginine transporter-deficient fibroblasts can sustain nitric oxide production. Nitric oxide : biology and chemistry 22 12446172
2017 The L530R variation associated with recurrent kidney stones impairs the structure and function of TRPV5. Biochemical and biophysical research communications 21 28847730
2013 A novel ion channel formed by interaction of TRPML3 with TRPV5. PloS one 21 23469151

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