Affinage

TRPV5

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

Length
729 aa
Mass
82.6 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPV5 is a constitutively active, highly Ca²⁺-selective tetrameric channel that serves as the rate-limiting apical Ca²⁺ entry step in active transcellular Ca²⁺ reabsorption in the renal distal convoluted tubule, and additionally participates in osteoclastic bone resorption (PMID:14679186, PMID:16291808). Channel gating is primarily controlled by PI(4,5)P₂ binding at the S4-S5/S6 interface, which opens the lower gate defined by Trp583, while Ca²⁺-dependent inactivation is mediated by calmodulin binding to the C-terminus (W702/R706), with CaM Lys116 forming a cation-π interaction with W583 to close the intracellular gate; PTH-stimulated PKA phosphorylation of Thr709 counteracts inactivation by displacing calmodulin (PMID:30305626, PMID:21576356, PMID:19423690, PMID:35476976). Surface abundance is regulated by a multi-layered trafficking network: klotho removes sialic acids from TRPV5 N-glycans to expose galectin-binding sites that retain the channel at the plasma membrane, PKC phosphorylation of Ser299/Ser654 inhibits caveolae-mediated endocytosis, the S100A10–annexin 2 complex is required for membrane targeting, Rab11a mediates clathrin-dependent recycling from perinuclear vesicles, and FGF23 signals through FGFR–αKlotho–ERK1/2–SGK1–WNK4 to promote apical TRPV5 expression (PMID:16239475, PMID:18606998, PMID:17006539, PMID:18305097, PMID:12660155, PMID:16354700, PMID:24434184). Extracellular protons inhibit gating via the pH sensor Glu522, which cooperates with intracellular pH-driven pore helix rotation and, at the structural level, by precluding PI(4,5)P₂ binding (PMID:14525991, PMID:16121193, PMID:35476976).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    TRPV5 knockout mice established TRPV5 as the essential apical Ca²⁺ entry channel for renal transcellular Ca²⁺ reabsorption, resolving a long-standing question about the molecular identity of the rate-limiting entry step.

    Evidence TRPV5⁻/⁻ mice with micropuncture, metabolic cage studies, and bone morphometry

    PMID:14679186

    Open questions at the time
    • Human loss-of-function genetics not reported
    • Relative contribution of TRPV5 vs TRPV6 in kidney not fully delineated
  2. 2003 High

    Defining the tetrameric architecture, subunit assembly domains, and pore topology resolved fundamental questions about TRPV5 channel stoichiometry and ion permeation pathway.

    Evidence Sucrose gradient sedimentation, co-IP, concatemer electrophysiology, systematic SCAM mapping of S5-pore-S6, and N/C-tail assembly domain mutagenesis

    PMID:12574114 PMID:14630907 PMID:15489237

    Open questions at the time
    • Full atomic structure of the channel was not yet available
    • Heterotetramer stoichiometry with TRPV6 in native tissue unknown
  3. 2003 High

    Identification of Glu522 as the extracellular pH sensor and the C-terminus (residues 649–701) as the Ca²⁺-dependent inactivation domain established the two key regulatory inputs controlling TRPV5 open probability.

    Evidence SCAM and single-channel recording with E522Q mutagenesis; C-terminal truncation series with patch clamp

    PMID:12634930 PMID:14525991

    Open questions at the time
    • Structural basis of pH-induced gating unknown
    • Identity of the C-terminal Ca²⁺ sensor (later shown to be calmodulin) not yet determined
  4. 2003 High

    Discovery that S100A10–annexin 2 binds the TRPV5 C-tail at Thr599 and is required for surface delivery established the first trafficking partner essential for channel function.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, T599A mutagenesis, annexin 2 siRNA knockdown with electrophysiology

    PMID:12660155

    Open questions at the time
    • Whether S100A10–annexin 2 acts in regulated vs constitutive trafficking unclear
  5. 2004 Medium

    Identification of 80K-H as a Ca²⁺-sensing modulator and SGK1/NHERF2 as trafficking regulators expanded the accessory protein network controlling TRPV5 activity and surface abundance.

    Evidence Co-IP and EF-hand mutagenesis for 80K-H; oocyte expression and PDZ domain deletions for NHERF2/SGK1

    PMID:15100231 PMID:15319523

    Open questions at the time
    • Direct binding site of 80K-H on TRPV5 not mapped
    • In vivo relevance of NHERF2 scaffold not tested
  6. 2005 High

    Three discoveries collectively established PI(4,5)P₂ as a key gating activator, klotho-mediated glycan remodeling as a membrane retention mechanism, and TRPV5 as essential for osteoclast bone resorption, broadening the channel's functional context beyond renal epithelium.

    Evidence Inside-out patch clamp with PIP₂/Mg²⁺ and D542 mutagenesis; β-glucuronidase assay and surface biotinylation for klotho; TRPV5⁻/⁻ osteoclast resorption pit assays

    PMID:16230466 PMID:16239475 PMID:16291808

    Open questions at the time
    • Structural basis of PIP₂ binding unknown at this point
    • Specific glycan residues modified by klotho unresolved
    • TRPV5 role in osteoblasts not addressed
  7. 2005 High

    Internal pH-driven pore helix rotation cooperates with the extracellular E522 pH sensor, revealing a two-sided conformational gating mechanism for proton inhibition.

    Evidence SCAM on pore helix residues combined with intracellular and extracellular pH manipulation and electrophysiology

    PMID:16121193

    Open questions at the time
    • Atomic details of the rotation not resolved until cryo-EM
  8. 2006 High

    Defining the calbindin-D28K association, Rab11a-mediated recycling, PKC phosphorylation sites (S299/S654) via tissue kallikrein, and pH-dependent vesicular trafficking built a comprehensive picture of how TRPV5 surface abundance is dynamically regulated.

    Evidence TIRF microscopy and primary DCT cells for calbindin-D28K; GST pulldown and dominant-negative Rab11a for recycling; site-directed mutagenesis S299A/S654A with primary cell Ca²⁺ assays for kallikrein/PKC; TIRF and surface labeling for pH-dependent trafficking

    PMID:16354700 PMID:16763551 PMID:17006539 PMID:17178838

    Open questions at the time
    • Whether calbindin-D28K binding is direct or involves intermediates debated
    • Endosomal sorting signals for recycling vs degradation not identified
  9. 2007 High

    Demonstration that TRPV5 undergoes constitutive clathrin/dynamin-dependent endocytosis into Rab11a-positive recycling compartments, with Ca²⁺-dependent recycling kinetics, unified earlier trafficking observations into a coherent constitutive cycling model.

    Evidence Dynamin/clathrin inhibition, Rab11a colocalization, pulse-chase, BAPTA-AM Ca²⁺ chelation

    PMID:18077461

    Open questions at the time
    • Molecular link between intracellular Ca²⁺ and recycling machinery not identified
  10. 2008 High

    The klotho mechanism was refined to sialidase-mediated removal of α2,6-linked sialic acids exposing galectin-1 binding sites, and PKC-mediated phosphorylation was shown to specifically inhibit caveolae-dependent endocytosis, distinguishing two parallel surface-retention pathways.

    Evidence ST6Gal-1 siRNA and complementation for galectin lattice; caveolin-1 KO cells and site-directed mutagenesis for caveolae pathway

    PMID:18305097 PMID:18606998

    Open questions at the time
    • Whether galectin-1 or galectin-3 is the physiologically relevant lectin in DCT was debated
  11. 2009 High

    PTH was shown to activate TRPV5 via cAMP–PKA phosphorylation of Thr709, increasing open probability without changing surface expression—a mechanism distinct from the PKC/surface-retention pathway—while CaR was found to activate TRPV5 through PKC at the same S299/S654 sites.

    Evidence FRET-based cAMP/Ca²⁺ sensors, in vitro PKA phosphorylation, T709A mutagenesis with patch clamp for PTH; Fura-2 imaging and mutagenesis for CaR

    PMID:19157541 PMID:19423690

    Open questions at the time
    • How PTH coordinates dual PKA and PKC arms at the channel level in vivo not resolved
  12. 2011 High

    NMR-based mapping of the calmodulin–TRPV5 C-terminal interaction at residue resolution (W702, R706) and demonstration that PKA phosphorylation of T709 reduces CaM affinity provided the molecular logic linking hormonal stimulation to relief of Ca²⁺-dependent inactivation.

    Evidence NMR spectroscopy with mutagenesis (W702A, R706E, T709) and patch clamp

    PMID:21576356

    Open questions at the time
    • Structural basis of how CaM occupancy gates the pore not yet visualized
  13. 2013 Medium

    Additional surface-retention mechanisms were identified: uromodulin inhibits caveolin-1-mediated endocytosis extracellularly, galectin-3 (not just galectin-1) activates TRPV5 in DCT, and inflammatory cytokines promote UBR4 E3 ligase-mediated ubiquitination and degradation counteracted by klotho.

    Evidence Caveolin-1 KO cells with UMOD application; N358Q glycan mutant and galectin-3 application; UBR4 co-IP and siRNA with klotho overexpression mouse model

    PMID:23466996 PMID:23747339 PMID:23970553

    Open questions at the time
    • Direct ubiquitination sites on TRPV5 not mapped
    • Relative importance of galectin-1 vs galectin-3 in vivo unresolved
    • UMOD mechanism confirmed only in cell lines
  14. 2014 High

    FGF23 was shown to promote TRPV5 apical membrane abundance via FGFR–αKlotho–ERK1/2–SGK1–WNK4, and NDPK-B histidine phosphorylation of H711 was identified as a novel activating modification reversed by PHPT1, adding two new regulatory axes.

    Evidence Fgf23 KO mouse with pathway inhibitor dissection; inside-out patch clamp with H711 mutagenesis and NDPK-B⁻/⁻ mouse

    PMID:24434184 PMID:24523290

    Open questions at the time
    • How WNK4 mechanistically increases TRPV5 surface expression not defined
    • Whether NDPK-B and PKA pathways converge at the C-terminus not tested
  15. 2018 High

    Cryo-EM structures of TRPV5 with PI(4,5)P₂, calmodulin, and the inhibitor econazole revealed the atomic basis of gating: PIP₂ opens the lower gate at the S4-S5/S6 interface, CaM closes it via a Lys116–Trp583 cation-π interaction, and econazole occupies a vanilloid-like pocket to lock the channel shut.

    Evidence Cryo-EM at near-atomic resolution with molecular dynamics simulations and functional validation

    PMID:29323279 PMID:30305626

    Open questions at the time
    • Open-state structure not captured
    • Lipid nanodisc structures needed for native-like context
  16. 2019 High

    Lipid nanodisc cryo-EM structures and the W583A gate mutant confirmed Trp583 as the intracellular gate and revealed flexible CaM binding stoichiometry, while structure-based screening identified novel selective TRPV5 inhibitors binding at a site distinct from the econazole pocket.

    Evidence Cryo-EM in lipid nanodiscs with W583A mutagenesis; virtual screening with cryo-EM validation and patch clamp

    PMID:30975749 PMID:31647410

    Open questions at the time
    • Full open-state structure still lacking
    • Pharmacokinetics and in vivo efficacy of novel inhibitors not reported
  17. 2022 High

    Cryo-EM at low pH captured intermediate conformations of the open-to-closed transition and showed that acidification inhibits by precluding PIP₂ binding, confirming PIP₂ as the primary gating modulator and reinterpreting PKA's role as preventing CaM binding rather than directly activating gating.

    Evidence Cryo-EM structures at different pH values with electrophysiology

    PMID:35476976

    Open questions at the time
    • Complete gating cycle with all modulators simultaneously bound not captured
    • Native tetrameric composition (homo vs hetero with TRPV6) in DCT not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full open-state structure, the in vivo stoichiometry of TRPV5/TRPV6 heterotetramers in native tissue, the direct ubiquitination sites mediating cytokine-induced degradation, human genetic validation of TRPV5 loss-of-function phenotypes, and the therapeutic potential of selective TRPV5 modulators.
  • Full open-state cryo-EM structure not yet captured
  • No human Mendelian disease mutation reported
  • In vivo pharmacology of TRPV5-selective inhibitors untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 9 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-382551 Transport of small molecules 4
Partners
ANXA2CALB1CALM1KLNHERF2RAB11AS100A10TRPV6
Complex memberships
S100A10-annexin 2 complexTRPV5 homotetramerTRPV5-TRPV6 heterotetramer

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TRPV5 knockout mice display severely impaired active Ca2+ reabsorption in the early distal convoluted tubule, hypercalciuria, compensatory intestinal Ca2+ hyperabsorption, and reduced trabecular and cortical bone thickness, establishing TRPV5 as the key apical Ca2+ entry channel for active renal Ca2+ reabsorption. Genetic knockout (TRPV5-/- mice), in vivo micropuncture, metabolic cage studies, bone morphometry The Journal of clinical investigation High 14679186
2003 TRPV5 and TRPV6 form homotetramers (~400 kDa) and can assemble into heterotetramers with each other; N- and C-terminal intracellular tails mediate subunit assembly, and heterotetrameric complexes display distinct Ca2+-dependent inactivation, ion selectivity, and pharmacological block compared to homotetramers. Sucrose gradient sedimentation, co-immunoprecipitation, concatemer electrophysiology with pore mutants, HEK293 patch-clamp The EMBO journal High 12574114
2003 S100A10 binds the conserved VATTV motif (specifically Thr599) in the TRPV5 C-terminal tail, and the S100A10–annexin 2 complex is required to route TRPV5 to the plasma membrane; mutation T599A or siRNA knockdown of annexin 2 abolishes surface expression and channel activity. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, electrophysiology The EMBO journal High 12660155
2005 Klotho, acting as a beta-glucuronidase, hydrolyzes extracellular N-linked oligosaccharides on TRPV5, trapping the channel in the plasma membrane and sustaining Ca2+ channel activity in the kidney. Enzymatic activity assay (beta-glucuronidase), Ca2+ influx measurements in transfected cells, cell-surface biotinylation Science High 16239475
2005 PIP2 activates TRPV5 and protects against Mg2+-induced slow channel inhibition; intracellular Mg2+ binding to the selectivity filter (Asp542) causes both fast voltage-dependent block and a slower conformational change leading to channel closure, and PIP2 prevents the latter without affecting Mg2+ binding to the selectivity filter. Whole-cell and inside-out patch clamp, site-directed mutagenesis (D542), PIP2 application and PLC activation The Journal of general physiology High 16230466
2005 TRPV5 is essential for osteoclastic bone resorption; TRPV5 localizes to the osteoclast ruffled border membrane, and TRPV5-/- osteoclasts show increased numbers but severely impaired Ca2+ resorption activity in pit assays. TRPV5-/- mouse analysis, immunostaining, bone marrow culture, resorption pit assay, urine deoxypyridinoline measurement Proceedings of the National Academy of Sciences of the United States of America High 16291808
2006 Calbindin-D28K directly associates with TRPV5 at low intracellular Ca2+ concentrations, translocating to the plasma membrane; this association buffers Ca2+ flux near the TRPV5 pore, preventing Ca2+-dependent inactivation and enabling high Ca2+ transport rates. Protein-binding analysis, subcellular fractionation, evanescent-field (TIRF) microscopy, 45Ca2+ uptake, electrophysiology, primary connecting tubule/DCT cells The EMBO journal High 16763551
2006 GDP-bound Rab11a directly interacts with a conserved C-terminal stretch of TRPV5 and co-localizes with TRPV5 in sub-apical vesicles; dominant-negative GDP-locked Rab11a reduces surface expression and Ca2+ uptake, identifying Rab11a as a direct cargo-interacting trafficking GTPase for TRPV5. GST pulldown, co-immunoprecipitation, live imaging, 45Ca2+ uptake, surface biotinylation Molecular and cellular biology High 16354700
2006 Tissue kallikrein (TK) stimulates Ca2+ reabsorption via bradykinin receptor type 2 → PLC/DAG/PKC pathway, phosphorylating TRPV5 at Ser299 and Ser654 to increase its plasma membrane abundance by delaying retrieval; mutation of these PKC sites abolishes the effect. Primary renal epithelial cell cultures, pharmacological inhibitors, site-directed mutagenesis (S299A, S654A), cell-surface labeling, 45Ca2+ assays, electrophysiology The EMBO journal High 17006539
2006 Extracellular pH dynamically controls TRPV5 surface abundance via vesicular 'kiss and linger' interactions: alkalinization recruits TRPV5-containing vesicles to the membrane increasing activity, while acidification retrieves them, as demonstrated by TIRF microscopy and functional assays. TIRF microscopy, cell-surface protein labeling, electrophysiology, 45Ca2+ uptake, functional channel recovery after chemobleaching Molecular and cellular biology High 17178838
2003 Extracellular glutamate 522 (E522) in the pore region of TRPV5 acts as the pH sensor; its mutation (E522Q) selectively abolishes proton-induced reduction of open probability without affecting Mg2+-dependent block, and E522 is accessible from the extracellular face as shown by MTSET reactivity of the E522C mutant. Whole-cell and single-channel patch clamp, site-directed mutagenesis, substituted cysteine accessibility (MTS reagents) The Journal of biological chemistry High 14525991
2005 Internal protons cause a clockwise rotation of the pore helix in TRPV5 (detected by SCAM), which facilitates closing of the selectivity filter gate by external protons; intra- and extracellular pH sensors cooperate through this conformational change. Substituted cysteine accessibility method (SCAM), whole-cell patch clamp, site-directed mutagenesis The EMBO journal High 16121193
2004 The N-tail (residues 64–77) and C-tail (residues 596–601) of TRPV5 mediate channel subunit assembly via N-N, C-C, and N-C interactions; deletion of either tail alone exerts dominant-negative effects on surface trafficking, whereas dual deletion does not, establishing these domains as assembly signals required for plasma membrane targeting. GST pulldown, co-immunoprecipitation, patch clamp, 45Ca2+ uptake in Xenopus oocytes, surface expression analysis The Journal of biological chemistry High 15489237
2004 80K-H, a Ca2+-binding protein with two EF-hand structures, directly binds TRPV5 and acts as a Ca2+ sensor controlling channel activity; inactivation of its EF-hands reduces TRPV5-mediated Ca2+ current and accelerates Ca2+-dependent feedback inhibition without altering TRPV5 surface expression. cDNA microarray, co-immunoprecipitation, electrophysiology, site-directed mutagenesis of EF-hands The Journal of biological chemistry High 15100231
2008 Klotho removes alpha2,6-linked sialic acids from TRPV5 N-glycan chains via its sialidase activity, exposing galactose-N-acetylglucosamine that then binds galectin-1 to form a cell-surface lattice retaining functional TRPV5 at the plasma membrane; knockdown of ST6Gal-1 or use of hamster cells lacking ST6Gal-1 abolishes the effect. siRNA knockdown of sialyltransferases, heterologous expression in cells lacking ST6Gal-1, Ca2+ influx measurements, surface abundance assays Proceedings of the National Academy of Sciences of the United States of America High 18606998
2008 TRPV5 undergoes constitutive caveolae-mediated endocytosis; PKC activation (via OAG or PTH) phosphorylates TRPV5 at Ser299 and Ser654 to inhibit this endocytosis, increasing surface abundance; caveolin-1 knockdown or knockout abolishes the PKC-mediated upregulation. Dominant-negative dynamin, siRNA knockdown of caveolin-1 and clathrin, caveolin-1 KO cells, site-directed mutagenesis, patch clamp, surface biotinylation American journal of physiology. Renal physiology High 18305097
2009 PTH activates TRPV5 via the adenylyl cyclase–cAMP–PKA cascade; PKA directly phosphorylates Thr709 on TRPV5, increasing channel open probability without changing surface expression; alanine substitution at T709 abolishes both in vitro phosphorylation and PTH-mediated stimulation. FRET (cAMP and Ca2+ dynamics), cell-surface biotinylation, patch clamp with PKA catalytic subunit application, site-directed mutagenesis (T709A), in vitro phosphorylation assay Journal of the American Society of Nephrology High 19423690
2007 TRPV5 is constitutively internalized via dynamin- and clathrin-dependent endocytosis into Rab11a-positive perinuclear recycling vesicles; after internalization, TRPV5 is stable (>3 h) and recycles back to the surface, and this recycling is Ca2+-dependent (BAPTA-AM reduces recycling kinetics). Dynamin and clathrin inhibition, Rab11a colocalization, pulse-chase experiments, Ca2+ chelation (BAPTA-AM), brefeldin A block The Journal of biological chemistry High 18077461
2011 Calmodulin (CaM) binds Ca2+-dependently to the last ~30 residues of the TRPV5 C-terminus (W702, R706), with one CaM bridging two TRPV5 C-termini; this interaction mediates Ca2+-dependent inactivation of the channel. PTH-induced PKA phosphorylation of T709 reduces CaM binding, thereby increasing TRPV5 open probability. NMR spectroscopy (residue-level interaction mapping), site-directed mutagenesis (W702A, R706E, T709), patch clamp electrophysiology Molecular and cellular biology High 21576356
2018 Cryo-EM structures of TRPV5 bound to PI(4,5)P2 or calmodulin reveal: PI(4,5)P2 binds between the N-linker, S4-S5 linker, and S6 helix, inducing conformational changes that open the lower gate; CaM binds two TRPV5 C-terminal peptides simultaneously, and Ca2+-activated CaM Lys116 forms a cation-π interaction with Trp583 at the intracellular gate to mediate channel inhibition. Cryo-electron microscopy (cryo-EM), molecular dynamics simulations, functional validation Nature communications High 30305626
2018 Cryo-EM structure of full-length rabbit TRPV5 in complex with econazole reveals that econazole occupies a hydrophobic pocket analogous to the phosphatidylinositide/vanilloid pocket of TRPV1, locking TRPV5 in a closed conformation with a distinct lower gate that occludes Ca2+ permeation. Cryo-electron microscopy (cryo-EM), molecular dynamics simulations Nature structural & molecular biology High 29323279
2019 Cryo-EM structures of full-length TRPV5 in lipid nanodiscs and in complex with CaM reveal flexible CaM binding stoichiometry; the W583A gate mutant structure provides mechanistic insight into Ca2+-dependent regulation and confirms W583 as the intracellular gate. Cryo-electron microscopy in lipid nanodiscs, site-directed mutagenesis (W583A) Proceedings of the National Academy of Sciences of the United States of America High 30975749
2014 FGF23 promotes renal Ca2+ reabsorption and increases apical membrane abundance of TRPV5 via a signaling cascade involving FGF receptor–αKlotho complex, ERK1/2, SGK1, and WNK4; Fgf23 knockout mice show reduced TRPV5 membrane abundance and Ca2+ reabsorption similar to αKlotho knockouts. Fgf23 KO mouse analysis, pharmacological pathway dissection (ERK1/2, SGK1, WNK4 inhibitors/activators), immunostaining, colocalization studies The EMBO journal High 24434184
2014 NDPK-B (histidine kinase) activates TRPV5 channel activity and Ca2+ flux by phosphorylating histidine 711 in the C-terminal tail; PHPT1 (histidine phosphatase) reverses this activation. NDPK-B knockdown reduces TRPV5 activity, and NDPK-B-/- mice have increased urinary Ca2+ excretion. Inside-out patch clamp, site-directed mutagenesis (H711), shRNA knockdown, NDPK-B-/- mouse urinary Ca2+ measurement Molecular biology of the cell High 24523290
2006 WNK4 increases TRPV5-mediated Ca2+ uptake twofold by enhancing TRPV5 surface expression when co-expressed in Xenopus oocytes; this effect requires complex N-glycosylation of TRPV5 and is abolished by blocking the secretory pathway or by the N358Q glycosylation-null mutant. Xenopus oocyte expression, 45Ca2+ uptake, surface expression analysis, N-glycosylation mutant (N358Q), syntaxin 6 blockade American journal of physiology. Renal physiology Medium 17018846 18703016
2009 Ca2+-sensing receptor (CaR) co-localizes with TRPV5 at the DCT/CNT luminal membrane and activates TRPV5-mediated Ca2+ influx via PMA-insensitive PKC isoforms targeting Ser299 and Ser654; mutation of these residues or dominant-negative CaR abolishes stimulation. Co-localization immunostaining, patch clamp, Fura-2 Ca2+ imaging, site-directed mutagenesis (S299A, S654A), dominant-negative CaR(R185Q) Cell calcium Medium 19157541
2005 FKBP52 specifically interacts with TRPV5 and inhibits channel activity; the peptidyl-prolyl cis-trans isomerase (PPIase) catalytic domain of FKBP52 is required for this inhibition, as shown by PPIase-domain mutation and FK-506 pharmacological block. Co-immunoprecipitation, 45Ca2+ uptake, electrophysiology, siRNA knockdown, pharmacological blockade (FK-506), PPIase domain mutagenesis American journal of physiology. Renal physiology Medium 16352746
2004 SGK1 (but not SGK2) and the scaffold protein NHERF2 cooperate to stimulate TRPV5-mediated Ca2+ transport by increasing TRPV5 plasma membrane abundance; the second PDZ domain of NHERF2 is required for this effect, and the TRPV5 C-tail interacts with NHERF2 in a Ca2+-independent manner. Xenopus oocyte expression, 45Ca2+ uptake, electrophysiology, pull-down/overlay assays, PDZ domain deletion mutants Cellular physiology and biochemistry Medium 15319523 15665527
2013 Uromodulin (UMOD) upregulates TRPV5 current density and surface abundance by impeding caveolin-1-mediated endocytosis from the extracellular side; UMOD has no effect in caveolin-1 null cells and requires caveolin-1 re-expression to restore regulation. Disease mutant UMOD fails to upregulate TRPV5. Patch clamp, surface biotinylation, caveolin-1 KO cells, extracellular UMOD application, immunofluorescence in Umod-/- mice Kidney international Medium 23466996
2016 MUC1 physically interacts with TRPV5 (co-immunoprecipitation) and upregulates its activity by impairing dynamin-2- and caveolin-1-mediated endocytosis; this effect requires TRPV5 N-glycan and is mediated through a galectin-3 lattice binding to MUC1 VNTRs; disease-mutant MUC1 fails to increase TRPV5 activity. Patch clamp, co-immunoprecipitation, siRNA knockdown of galectin-1 and galectin-3, dynamin-2/caveolin-1 inhibition, VNTR-deletion mutant Journal of the American Society of Nephrology Medium 27036738
2003 The C-terminus of TRPV5 (specifically residues 649–701) controls Ca2+-dependent inactivation; deletion of the last 30 amino acids (G701X) or truncation at positions 650–653 decreases Ca2+ sensitivity, while E649X abolishes Ca2+-dependent inactivation entirely. C-terminal truncation mutagenesis, patch clamp electrophysiology, HEK293 heterologous expression Pflugers Archiv Medium 12634930
2017 Trp583 at the intracellular pore terminus of TRPV5 acts as a gate hinge for Ca2+ permeation; W583 mutants display massively increased Ca2+ influx, and structural modeling combined with electrophysiology indicates a glycine residue above W583 provides flexibility for gate rearrangement; this gate also functionally interacts with the C-terminus involved in CaM-mediated inactivation. Site-directed mutagenesis, patch clamp electrophysiology, homology modeling, biochemical analysis Scientific reports Medium 28374795
2022 Cryo-EM shows low extracellular pH inhibits TRPV5 by precluding PI(4,5)P2 binding/activation and captures intermediate conformations during the open-to-closed transition; PKA phosphorylation controls TRPV5 activity by preventing CaM binding rather than directly activating gating, and PI(4,5)P2 is the primary gating modulator. Cryo-electron microscopy, electrophysiology Cell reports High 35476976
2013 Inflammatory cytokines (TNF-α, IFN-γ, IL-1β) reduce TRPV5 surface expression by promoting its interaction with UBR4 E3 ubiquitin ligase, leading to ubiquitin-dependent degradation; klotho protects TRPV5 from this cytokine-induced endocytosis and degradation. Co-immunoprecipitation (TRPV5-UBR4), UBR4 siRNA knockdown, adenoviral TRPV5 expression in mIMCD3 cells, transgenic Klotho overexpression mouse model Gastroenterology Medium 23747339
2014 Klotho upregulates TRPV5 from both inside and outside the cell: extracellular (secreted) Klotho inhibits TRPV5 endocytosis (blocked by dominant-negative dynamin), while intracellular (membrane-bound) Klotho enhances forward trafficking (blocked by brefeldin A); both effects require the putative sialidase activity of Klotho. Patch clamp, dominant-negative dynamin II, brefeldin A, sialidase-activity site mutagenesis, HEK293 coexpression The Journal of biological chemistry Medium 25378396
2013 Klotho and sialidase stimulate TRPV5 by two distinct mechanisms: klotho acts via the TRPV5 N-glycan (N358Q mutant abolishes klotho effect) to inhibit endocytosis, while sialidase increases TRPV5 activity by inhibiting lipid raft-mediated internalization independently of N-glycosylation; galectin-3 (not galectin-1) is expressed in DCT and activates TRPV5. Biochemical glycan assays, 45Ca2+ uptake, TIRF microscopy, N-glycosylation mutant (N358Q), galectin-3 application The Journal of biological chemistry Medium 23970553
2003 SCAM mapping of the TRPV5 outer pore reveals that the S5-to-pore region (L520C, G521C, E522C) is accessible from the extracellular medium, the pore helix (Pro527–Ile541) adopts an alpha-helical structure with a cation-selective interior, and Asp542 is at the center of the selectivity filter. Substituted cysteine accessibility method (SCAM) with MTSET/MTSES, whole-cell patch clamp, 44 position cysteine scan The Journal of biological chemistry Medium 14630907
2019 Structure-based virtual screening identified novel specific TRPV5 inhibitors; cryo-EM of TRPV5 with the selective inhibitor revealed binding sites distinct from the econazole pocket, enabling a proposed mechanism of selective TRPV5 inhibition over TRPV6. Structure-based virtual screening, cryo-electron microscopy, patch clamp electrophysiology eLife Medium 31647410

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.) 517 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 336 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 193 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 165 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 134 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
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