Affinage

CLCN3

H(+)/Cl(-) exchange transporter 3 · UniProt P51790

Length
818 aa
Mass
91.0 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLCN3 encodes ClC-3, an intracellular Cl⁻/H⁺ antiporter that provides charge compensation for V-ATPase-driven acidification of endosomes, lysosomes, synaptic vesicles, and insulin secretory granules, thereby supporting lysosomal degradation, neurotransmitter loading, and insulin granule priming (PMID:12059962, PMID:21378974, PMID:19808023, PMID:17977943). ClC-3 splice variants are differentially targeted to late endosomes/lysosomes or recycling endosomes via N-terminal dileucine and isoleucine-proline motifs through clathrin- and AP-3-dependent trafficking, and ClC-3 heterodimerizes with ClC-4 to direct ClC-4 compartmental sorting (PMID:26342074, PMID:17652080, PMID:15073168, PMID:28972156). At the plasma membrane, CaMKII phosphorylation at S109 and ROCK2 phosphorylation at T532 activate ClC-3-mediated Cl⁻ efflux that drives cell volume regulation, premitotic cytoplasmic condensation, and cell migration, while within signaling endosomes ClC-3 provides charge neutralization for Nox1-dependent ROS production and downstream NF-κB activation (PMID:14754994, PMID:26562480, PMID:18784301, PMID:17673675). De novo missense and homozygous loss-of-function variants in CLCN3 cause neurodevelopmental disorders with global developmental delay, intellectual disability, and structural brain abnormalities (PMID:34186028).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 Medium

    Cloning of CLCN3 established it as a member of the voltage-gated chloride channel family with predominant expression in neuroectoderm-derived tissues, raising the question of its physiological ion transport role.

    Evidence Molecular cloning, sequence analysis, and Northern blot/in situ hybridization in human tissues

    PMID:7665160

    Open questions at the time
    • No functional electrophysiology performed
    • Endogenous subcellular localization not determined
  2. 1999 High

    Identification of PKC phosphorylation at S51 as a volume-sensing regulatory mechanism and CaMKII as an activator established that ClC-3 channel activity is under bidirectional kinase control at the plasma membrane.

    Evidence Site-directed mutagenesis and patch-clamp in cardiac cells and NIH/3T3 overexpression systems; CaMKII infusion in tsA cells with surface biotinylation

    PMID:11274166 PMID:9874688

    Open questions at the time
    • Whether CaMKII phosphorylation site was identified at this stage
    • Physiological context of dual kinase regulation unclear
  3. 2000 High

    Heterologous expression revealed ClC-3 produces extremely outward-rectifying, swelling-insensitive currents identical to ClC-5, challenging the simple model that ClC-3 is the canonical volume-sensitive anion channel.

    Evidence Transient transfection in CHO-K1 cells with whole-cell patch-clamp and pharmacological profiling

    PMID:10973952

    Open questions at the time
    • Apparent conflict with endogenous VSOAC data not resolved
    • Cell-type-specific differences in ClC-3 function not addressed
  4. 2002 High

    Multiple convergent studies established ClC-3 as a predominantly intracellular protein required for endosomal/lysosomal acidification: Clcn3⁻/⁻ mice showed elevated endosomal pH, neuronal ceroid lipofuscinosis-like neurodegeneration, and lysosomal storage, while overexpression promoted LAMP-1-positive acidic vesicle formation dependent on the E224 gating glutamate.

    Evidence Targeted gene disruption in mice with endosomal pH measurement and histology; heterologous overexpression with E224A mutagenesis and lysosomal marker co-localization

    PMID:11997263 PMID:12059962

    Open questions at the time
    • Mechanism of V-ATPase coupling not biochemically defined
    • Relative contribution of Cl⁻ channel vs. antiporter mode not yet resolved
  5. 2002 High

    AP-3-dependent sorting to synaptic vesicles was demonstrated using the mocha mouse model, linking ClC-3 trafficking to presynaptic function and vesicular zinc transport alongside ZnT3.

    Evidence AP-3-deficient mocha mice, subcellular fractionation, brefeldin A treatment, ZnT3 co-fractionation and zinc transport assay in PC-12 cells

    PMID:15073168

    Open questions at the time
    • Direct role in neurotransmitter loading not yet tested
    • Relative contribution of AP-3 vs. clathrin pathways not quantified
  6. 2004 High

    Identification of S109 as the specific CaMKII phosphorylation site responsible for plasma membrane Cl⁻ conductance activation provided a defined molecular mechanism for kinase-dependent ClC-3 regulation.

    Evidence In vitro kinase assay, S109A mutagenesis, whole-cell patch-clamp with CaMKII infusion in smooth muscle and HT29 cells, Clcn3⁻/⁻ negative control

    PMID:14754994

    Open questions at the time
    • Whether S109 phosphorylation alters trafficking versus gating not distinguished
    • In vivo phosphorylation stoichiometry unknown
  7. 2007 High

    Several key mechanistic features were resolved simultaneously: (1) ClC-3 operates as a coupled Cl⁻/H⁺ antiporter gated by the E224 glutamate, (2) clathrin-mediated endocytosis via an N-terminal dileucine motif keeps ClC-3 predominantly intracellular, (3) ClC-3 in signaling endosomes provides charge neutralization for Nox1 NADPH oxidase enabling TNFα/IL-1β-induced ROS production and NF-κB activation, and (4) F-actin binding to the C-terminus is required for hypotonic activation.

    Evidence Overexpression with pH manipulation and E224A mutagenesis for antiport; co-IP and mutagenesis of dileucine motif for trafficking; co-IP with Nox1, shRNA, and NF-κB reporter for endosomal ROS; GST pulldown with F-actin and peptide competition with patch-clamp for cytoskeletal interaction

    PMID:17442672 PMID:17652080 PMID:17673675 PMID:17977943

    Open questions at the time
    • Structural basis of Cl⁻/H⁺ coupling unknown
    • How Nox1-ClC-3 coupling is regulated remains unclear
    • F-actin interaction domain not structurally characterized
  8. 2008 High

    ClC-3 was shown to participate in diverse cellular processes beyond ion transport: premitotic cytoplasmic condensation during cell division, CaMKII-dependent glioma invasion, endosomal-dependent exocytosis in chromaffin cells, postsynaptic modulation of NMDA receptor responses, and cardiac VSOAC activity essential for cardioprotection.

    Evidence Patch-clamp at defined cell cycle stages with shRNA; co-IP of ClC-3 with CaMKII in glioma biopsies and invasion assays; Clcn3⁻/⁻ chromaffin cell capacitance measurements; co-IP with NMDA receptors and surface biotinylation in hippocampal neurons with Clcn3⁻/⁻ comparison; cardiac-specific inducible knockout with echocardiography

    PMID:17046694 PMID:18784301 PMID:18923035 PMID:19615374 PMID:20139089

    Open questions at the time
    • Molecular basis of ClC-3/NMDA receptor interaction not defined
    • Whether cardiac hypertrophy is directly due to loss of volume regulation or secondary effects unknown
    • Mechanism linking endosomal ClC-3 to LDCV exocytosis indirect
  9. 2009 High

    Two studies defined the biophysical basis and physiological scope of ClC-3 antiport: pH-dependent uncoupling of Cl⁻/H⁺ exchange at low luminal pH was characterized, and ClC-3 on insulin secretory granules was shown essential for granule acidification and priming, with >60% reduction in insulin secretion in Clcn3⁻/⁻ beta cells.

    Evidence Systematic pH manipulation with E224A and cysteine mutagenesis in HEK293 cells; Clcn3⁻/⁻ beta cells with insulin secretion assays, capacitance measurements, and immuno-EM of LDCVs

    PMID:19808023 PMID:19926787

    Open questions at the time
    • Physiological relevance of uncoupling at extreme pH not clear
    • Whether impaired insulin secretion contributes to metabolic phenotype in vivo not tested
  10. 2011 High

    Presynaptic ClC-3 on GABAergic synaptic vesicles was shown essential for inhibitory neurotransmission by enabling Cl⁻-dependent vesicle acidification and GABA loading, while CaMKII-phosphorylated ClC-3 at postsynaptic sites was found to limit long-term potentiation magnitude.

    Evidence Hippocampal slice electrophysiology and vesicle acidification assays in Clcn3⁻/⁻ mice; LTP recordings with phospho-site decoy peptide

    PMID:21378974 PMID:23165767

    Open questions at the time
    • Whether ClC-3 is the sole vesicular Cl⁻/H⁺ exchanger on inhibitory SVs not resolved
    • Mechanism by which postsynaptic ClC-3 constrains LTP expression unknown
  11. 2012 High

    ClC-3 deficiency leads to larger synaptic vesicles with increased glutamate content and enhanced excitatory transmission, providing a mechanism for excitotoxic neurodegeneration, while in VSMCs ClC-3 was confirmed as necessary for CaMKII-dependent migration regulated by Ins(3,4,5,6)P4.

    Evidence Patch-clamp with γ-DGG antagonism and EM of SVs in Clcn3⁻/⁻ hippocampal neurons; ClC-3 null VSMCs with CaMKII inhibitor and Ins(3,4,5,6)P4 in transwell migration

    PMID:23150504 PMID:24904288

    Open questions at the time
    • Whether altered SV size is a direct consequence of antiport loss or secondary adaptation unknown
    • How Ins(3,4,5,6)P4 binding inhibits ClC-3 structurally is undefined
  12. 2015 High

    Characterization of three ClC-3 splice variants revealed isoform-specific targeting motifs directing differential endosomal compartment sorting while preserving identical Cl⁻/H⁺ exchange, explaining how a single gene supports functions in multiple compartments.

    Evidence Splice variant identification in mouse brain, mutagenesis of N-terminal dileucine and IP motifs, co-localization with compartment markers, electrophysiology

    PMID:26342074

    Open questions at the time
    • Relative expression of each isoform across tissues not quantified
    • Functional consequence of isoform-specific sorting in vivo not tested
  13. 2016 High

    ROCK2 phosphorylation at T532 was identified as a third kinase regulatory input activating ClC-3 at the plasma membrane downstream of angiotensin II, linking ClC-3 to vascular remodeling.

    Evidence Co-IP, T532D/T532A mutagenesis, ROCK2 siRNA, patch-clamp, transwell migration, ClC-3 null mice cerebrovascular phenotype

    PMID:26562480

    Open questions at the time
    • Whether PKC, CaMKII, and ROCK2 regulate ClC-3 cooperatively or independently at the same channels unknown
    • Structural basis of T532 regulation not defined
  14. 2017 High

    ClC-3 was established as the obligate heterodimerization partner directing ClC-4 out of the ER to endosomal compartments, revealing a non-cell-autonomous trafficking function.

    Evidence Heterologous co-expression, Clcn3⁻/⁻ astrocytes showing ClC-4 ER retention, clear native PAGE demonstrating stable ClC-3/ClC-4 heterodimers

    PMID:28972156

    Open questions at the time
    • Whether ClC-3/ClC-4 heterodimers have altered transport properties versus homodimers not tested
    • Stoichiometry of heterodimer not resolved
  15. 2018 High

    Detailed gating analysis revealed that coupled Cl⁻/H⁺ exchange depends on interaction between the external gating glutamate E224 and the central tyrosine gate Y572, with low luminal pH inhibiting transport—establishing the molecular basis for self-limiting acidification.

    Evidence Systematic mutagenesis (E224A, Y572S, Y572F, M531A) with gating charge analysis and cytoplasmic alkalization rate measurement

    PMID:29917234

    Open questions at the time
    • No high-resolution structure of ClC-3 available
    • Conformational dynamics of gate interaction not resolved
  16. 2021 High

    Human genetic evidence directly linked CLCN3 to neurodevelopmental disease: both loss-of-function and gain-of-function missense variants (p.Ile607Thr, p.Thr570Ile showing increased currents and loss of pH inhibition) cause GDD/ID with brain malformations, demonstrating bidirectional sensitivity to ClC-3 dysfunction.

    Evidence Whole-exome sequencing in affected families, electrophysiological characterization of variants in Xenopus oocytes and mammalian cells, clinical MRI

    PMID:34186028

    Open questions at the time
    • Pathogenic mechanism of gain-of-function variants at the cellular level not defined
    • Genotype-phenotype correlation across variant spectrum incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the high-resolution structure of ClC-3, the structural basis of Ins(3,4,5,6)P4 inhibition, how ClC-3 coordinates with V-ATPase stoichiometrically in different vesicle types, and whether gain-of-function and loss-of-function CLCN3 variants cause neurodegeneration through shared or distinct cellular mechanisms.
  • No cryo-EM or X-ray structure of ClC-3
  • Ins(3,4,5,6)P4 binding site not mapped
  • In vivo isoform-specific functions not dissected with conditional knockouts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 8 GO:0140657 ATP-dependent activity 4
Localization
GO:0005768 endosome 6 GO:0005886 plasma membrane 6 GO:0031410 cytoplasmic vesicle 4 GO:0005764 lysosome 3
Pathway
R-HSA-382551 Transport of small molecules 9 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-9609507 Protein localization 4 R-HSA-1640170 Cell Cycle 2
Partners
AP3B1CAMK2ACLCN4EBP50GRIN1ROCK2VDAC1
Complex memberships
ClC-3/ClC-4 heterodimer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CLCN3 encodes a 760-amino-acid protein belonging to the voltage-gated chloride channel (ClC) family, with high sequence similarity to GEF1 (a yeast integral membrane protein involved in respiration and iron-limited growth), indicating conserved fundamental function; the gene is expressed primarily in neuroectoderm-derived tissues, with high hippocampal, olfactory cortex, and olfactory bulb expression. Molecular cloning, sequence analysis, Northern blot/in situ hybridization Genomics Medium 7665160
1999 ClC-3 volume-regulated chloride channel activity is controlled by phosphorylation/dephosphorylation: PKC activation closes the channel, PKC inhibition opens it, and serine51 in the intracellular N-terminus (within a consensus PKC phosphorylation site) is the critical volume sensor residue. Site-directed mutagenesis, patch-clamp electrophysiology in cardiac cells and NIH/3T3 cells overexpressing ClC-3 The Journal of general physiology High 9874688
2000 When expressed in CHO-K1 cells, ClC-3 produces Cl->I- selective, extremely outward-rectifying currents insensitive to NPPB, DIDS, and phorbol esters and not activated by osmotic swelling—properties identical to ClC-5 and distinct from endogenous swelling-activated channels, demonstrating ClC-3 is not the swelling-activated channel under all conditions. Transient transfection of rat ClC-3 into CHO-K1 cells, whole-cell patch-clamp electrophysiology, pharmacological profiling The Journal of biological chemistry High 10973952
2001 CaMKII phosphorylation regulates the plasma membrane expression and activity of hCLC-3: intracellular infusion of autonomously active CaMKII increased ClC-3 currents ~22-fold in stably transfected tsA cells, and mutation of glycine 280 to glutamic acid in the pore region changed anion selectivity from I->Cl- to Cl->I-. Stable transfection of hCLC-3 in tsA cells, whole-cell patch-clamp with CaMKII infusion, AIP inhibitor, pore-region mutagenesis, surface biotinylation The Journal of biological chemistry High 11274166
2001 Intracellular dialysis of anti-ClC-3 antibody completely abolished expressed ClC-3 currents and native volume-sensitive outwardly rectifying anion channel (VSOAC) currents in guinea-pig cardiac cells, canine pulmonary arterial smooth muscle cells, and Xenopus oocytes, establishing ClC-3 as a major molecular entity of VSOACs in these cell types. Intracellular dialysis of polyclonal anti-ClC-3 antibody during whole-cell patch-clamp recording; antigen preabsorption controls The Journal of physiology High 11230516
2002 Heterologous ClC-3 expression in CHO-K1 and Huh-7 cells promotes lysosomal acidification: overexpression creates large acidic vesicles co-labeled with LAMP-1, LAMP-2, and cathepsin D; vesicle formation requires both V-ATPase proton pumping and ClC-3 Cl- channel activity (blocked by E224A mutant), consistent with ClC-3 providing charge neutralization for lysosomal acidification. Heterologous overexpression, bafilomycin treatment, E224A mutagenesis, organelle pH measurement, co-localization with lysosomal markers American journal of physiology. Cell physiology High 11997263
2002 CLC-3-deficient (Clcn3-/-) mice exhibit elevated endosomal pH, progressive neurodegeneration of hippocampus and retina, and lysosomal accumulation of mitochondrial F1F0 ATPase subunit c, phenocopying neuronal ceroid lipofuscinosis, establishing ClC-3 as required for endosomal acidification and lysosomal protein degradation. Targeted gene disruption (Clcn3-/- mice), endosomal pH measurement, immunohistochemistry, Western blot, histological analysis Genes to cells High 12059962
2002 ClC-3 antisense oligonucleotides significantly reduce volume-sensitive osmolyte and anion channel (VSOAC) density and impair regulatory volume decrease in HeLa cells and Xenopus oocytes, supporting ClC-3 as a fundamental molecular component of VSOACs. ClC-3 antisense transfection/injection, semi-quantitative and real-time PCR, immunoblot, hypotonic whole-cell recording, cell volume measurement The Journal of biological chemistry Medium 12183454
2002 ClC-3 is sorted to synaptic vesicles via an AP-3-dependent trafficking pathway; ClC-3 levels in synaptic vesicles and hippocampal mossy fiber terminals are reduced in AP-3-deficient mocha mice; in PC-12 cells ClC-3 trafficking to synaptic-like microvesicles is brefeldin A-sensitive; increased ClC-3 expression enhances vesicular zinc transport in concert with ZnT3, with which it co-segregates. AP-3-deficient mocha mouse model, subcellular fractionation, immunohistochemistry, brefeldin A treatment, ZnT3 co-fractionation and functional zinc transport assay The Journal of biological chemistry High 15073168
2002 ClC-3B, a novel C-terminal splice variant of ClC-3, interacts with the PDZ domain of EBP50 via a C-terminal PDZ-binding motif; co-transfection of ClC-3B with EBP50 redistributes ClC-3B to the leading edge of membrane ruffles and produces a remarkable increase in ORCC currents that can be activated by CFTR via PKA-dependent pathway. Cloning, in vitro and in vivo binding assays (GST pulldown, co-IP), immunofluorescence, whole-cell patch-clamp FASEB journal High 11967229
2004 CaMKII phosphorylates the N-terminus of CLC-3 in vitro, and serine 109 (S109) in the N-terminal CaMKII consensus sequence is critical for CaMKII-dependent Cl- conductance at the plasma membrane; S109A mutation abolishes the CaMKII-activated current. In vitro kinase phosphorylation assay, site-directed mutagenesis (S109A), whole-cell patch-clamp with CaMKII infusion in smooth muscle cells and HT29 cells, CLC-3-/- cells as negative control The Journal of physiology High 14754994
2004 Neuronal excitability is modulated by CLC-3 at postsynaptic sites: CaMKII-activated CLC-3 Cl- conductance enhances NMDA receptor-mediated miniature EPSPs in a Cl--dependent fashion; CLC-3 co-immunoprecipitates with NMDA receptors and is localized at postsynaptic sites by electron microscopy and surface biotinylation; this conductance is absent in clc-3-/- mice. Patch-clamp electrophysiology in hippocampal neurons, surface biotinylation, immunohistochemistry, electron microscopy, co-immunoprecipitation, clc-3-/- knockout comparison Neuron High 17046694
2007 ClC-3 overexpression in HEK293T cells induces pH-dependent outwardly rectifying currents with reversal potential shifts of ~10 mV/decade pH change and ~48 mV/decade Cl- change (non-Nernstian), indicating coupled Cl-/H+ antiport; E224A mutation removes pH sensitivity and restores Nernstian Cl- dependence, identifying E224 as the extracellular glutamate gate governing coupling. Heterologous overexpression in HEK293T, whole-cell patch-clamp, extracellular pH manipulation, E224A mutagenesis, reversal potential analysis American journal of physiology. Cell physiology High 17977943
2007 ClC-3 is primarily an intracellular transport protein that traffics through the plasma membrane via clathrin-mediated endocytosis; the N-terminal dileucine acidic cluster (amino acids 13-19) interacts directly with clathrin (demonstrated by co-IP and GST pulldown), and alanine replacement of this motif reduces endocytosis, increases plasma membrane expression, and abolishes clathrin binding. Pulse-labeling, surface biotinylation, immunofluorescence, co-immunoprecipitation, GST pulldown, alanine-substitution mutagenesis The Journal of biological chemistry High 17652080
2007 In vascular smooth muscle cells, Nox1 (NADPH oxidase subunit) and p22phox co-immunoprecipitate with early endosomal markers; ClC-3 co-localizes with Nox1 in early endosomes and is required for cytokine (TNF-α, IL-1β)-induced intraendosomal ROS production and subsequent NF-κB activation, functioning as a charge compensator for Nox1-generated electron flow across the endosomal membrane. Co-immunoprecipitation, co-localization by confocal microscopy, ROS measurement, NF-κB reporter assay, shRNA knockdown of ClC-3 Circulation research High 17673675
2007 Hypotonic activation of the short ClC-3 isoform (sClC-3) requires direct interaction between its cytosolic C-terminal tail and filamentous (F-) actin, but not G-actin; the F-actin binding region maps to amino acids 690-760, and peptides disrupting this interaction reduce VSOAC current density by ~40-60% upon intracellular dialysis. GST pulldown/co-sedimentation assays with F-actin, truncation mapping, synthetic peptide competition, intracellular dialysis with peptides + patch-clamp The Journal of biological chemistry High 17442672
2008 ClC-3 is required for CaMKII-dependent Cl- currents in glioma cells; CaMKII co-localizes and co-immunoprecipitates with ClC-3 in glioma cells and in GBM patient biopsies; shRNA knockdown of ClC-3 eliminates CaMKII-dependent currents, and inhibition of CaMKII reduces glioma invasion to the same extent as direct ClC-3 inhibition. Co-immunoprecipitation, whole-cell patch-clamp with CaMKII infusion, shRNA knockdown, AIP inhibitor, invasion assay The Journal of biological chemistry High 20139089
2008 ClC-3 channels are required for premitotic cytoplasmic condensation (PMC) during cell division: patch-clamp shows upregulation of Cl- currents at M phase; ClC-3 is present on the plasma membrane and at the mitotic spindle (co-localization and co-IP); shRNA knockdown of ClC-3 reduces M-phase Cl- currents, slows PMC rate, and impairs DNA condensation. Patch-clamp electrophysiology at defined cell cycle stages, co-immunoprecipitation, immunofluorescence co-localization, shRNA knockdown The Journal of neuroscience High 18784301
2008 Ins(3,4,5,6)P4 inhibits ClC-3-mediated Cl- conductance at the plasma membrane and raises intra-endosomal pH (inhibits ClC-3 Cl-/H+ exchange in endosomes), and also inhibits endogenous ClC-3 conductance in postsynaptic membranes of neonatal hippocampal neurons, identifying Ins(3,4,5,6)P4 as a physiological regulator of ClC-3. Heterologous expression in HEK293 cells, whole-cell patch-clamp, fluorescence ratio imaging of endosomal pH with FITC-transferrin, cell-permeant Ins(3,4,5,6)P4 analog Current biology High 18951024
2008 ClC-3 localizes to endosomes and synaptic-like microvesicles (not large dense-core vesicles) in adrenal chromaffin and pancreatic beta cells; Clcn3-/- chromaffin cells show decreased exocytosis of large dense-core vesicles (capacitance measurements and amperometry), indicating an indirect role of ClC-3 in LDCV exocytosis through endosomal trafficking steps. Immunohistochemistry, subcellular fractionation, capacitance measurements, carbon-fiber amperometry, Clcn3-/- knockout mice The Journal of neuroscience High 18923035
2009 ClC-3 Cl-/H+ exchange becomes uncoupled at low extracellular pH: between pH 8.2-6.2 protons shift the reversal potential, but below pH 6.2 Cl- transport and H+ transport uncouple; at pH 4.0 ClC-3 behaves as a purely anion-selective channel; extracellular cysteine residues (103-130 region) mediate MTSES-sensitivity; an E224A mutant lacks pH sensitivity and restores Nernstian Cl- dependence. Adenoviral ClC-3 expression in HEK293, whole-cell patch-clamp, pH and Cl- concentration manipulation, MTSES modification, mutagenesis (E224A, C103_P130del), shRNA knockdown of endogenous ClC-3 The Journal of biological chemistry High 19926787
2009 ClC-3 is expressed on insulin secretory granules in pancreatic beta cells and is required for granule priming: Clcn3-/- beta cells show >60% reduction in glucose- and sulfonylurea-evoked insulin secretion, ~80% reduction in depolarization-evoked exocytosis (capacitance measurements), and 44% reduction in proton transport across granule membranes; ClC-3 on LDCVs was confirmed by immunoblot, immunostaining, and immunoelectron microscopy. Clcn3-/- knockout mice, insulin secretion assay, single-cell capacitance measurements, vesicle proton transport assay, immunoblot/immunostaining/immuno-EM of purified LDCVs Cell metabolism High 19808023
2010 ClC-3 is a Cl-/H+ antiporter with biophysical properties similar to ClC-4 and ClC-5; an N-terminal retention signal keeps endogenous ClC-3 off the plasma membrane; N-terminal mutation (ClC-313-19A) allows surface expression and reveals outwardly rectifying coupled Cl-/H+ exchange; ClC-3 also exhibits large voltage-dependent nonlinear capacitance exceeding that of ClC-4 and ClC-5, and mutations of the proton glutamate decrease transport but increase capacitance. Electrophysiology combined with fluorescence pH measurements, N-terminal mutagenesis, proton glutamate mutagenesis, mathematical modeling ACS chemical neuroscience High 23509947
2010 TNF-α activates swelling-activated Cl- current (ICl,swell) in vascular smooth muscle cells via ClC-3-dependent endosomal H2O2 production: ICl,swell was absent in ClC-3 null cells, was activated by H2O2, was blocked by catalase, and was abolished by dominant-negative Rab5 or Rab11 (disrupting endosome trafficking), establishing a mechanistic link between ClC-3 endosomal ROS generation and ICl,swell activation. Perforated patch-clamp, ClC-3 null mouse VSMCs, catalase treatment, dominant-negative Rab5/Rab11 expression, H2O2 challenge The Journal of biological chemistry High 20479003
2011 Presynaptic CLC-3 on GABAergic synaptic vesicles is required for normal inhibitory transmission in hippocampus: Clcn3-/- slices show decreased amplitude and frequency of miniature IPSCs; CLC-3 co-localizes with VGAT in CA1; Cl--dependent acidification of inhibitory synaptic vesicles is markedly reduced in Clcn3-/- neurons, indicating CLC-3 enables neurotransmitter loading by supporting vesicle acidification. Hippocampal slice electrophysiology, immunofluorescence co-localization with VGAT, vesicle acidification assay with Cl- dependence, Clcn3-/- knockout Nature neuroscience High 21378974
2011 CaMKII-dependent kinase activation of ClC-3 drives cytoplasmic condensation (PMC) during mitotic cell rounding in human glioma cells; time-lapse microscopy shows PMC is reduced by ClC-3 shRNA knockdown or KN-93 (CaMKII inhibitor); CaMKII activates ClC-3 Cl- currents in dividing cells, leading to Cl- efflux-driven volume decrease. Time-lapse microscopy, patch-clamp electrophysiology at mitosis, shRNA knockdown of ClC-3, CaMKII inhibitor KN-93 American journal of physiology. Cell physiology High 22049206
2011 CLC-3 co-localizes with NMDA receptors at postsynaptic sites and its phosphorylation by CaMKII is required for its regulatory function in long-term potentiation (LTP): CLC-3 knockout increases LTP by ~40% above wild type; a decoy peptide of the CaMKII phosphorylation site on CLC-3 mimics the knockout effect on LTP, demonstrating that phosphorylated CLC-3 limits synaptic potentiation. Hippocampal slice LTP recordings, CLC-3 knockout mice, decoy phosphorylation peptide intracellular infusion The Journal of physiology High 23165767
2012 ClC-3 deficiency results in larger synaptic vesicles and increased amplitude/frequency of miniature EPSCs and action-potential-evoked EPSCs in hippocampal neurons; low-affinity AMPA receptor antagonist γ-DGG reduces quantal size more in WT than Clcn3-/- neurons, indicating ClC-3 controls glutamate loading into synaptic vesicles and affects release probability, with excessive glutamate release as a likely basis of neurodegeneration. Whole-cell patch-clamp in cultured hippocampal neurons from Clcn3-/- mice, γ-DGG and NBQX receptor antagonism, electron microscopy of synaptic vesicle size, measurement of readily releasable pool Frontiers in cellular neuroscience High 24904288
2013 Bradykinin-induced glioma chemotaxis requires CaMKII-dependent activation of ClC-3: bradykinin raises intracellular Ca2+, activates Ca2+-dependent Cl- currents via CaMKII→ClC-3 and KCa3.1; pharmacological CaMKII inhibition or shRNA knockdown of ClC-3 each inhibit Ca2+-activated Cl- currents and abolish bradykinin-induced chemotaxis; ClC-3 and KCa3.1 co-localize to invading processes of glioma cells. Fura-2 Ca2+ imaging, perforated patch-clamp electrophysiology, CaMKII inhibition, ClC-3 shRNA knockdown, brain slice invasion assay, immunofluorescence co-localization The Journal of neuroscience High 23345219
2014 ClC-3 deficiency promotes intestinal epithelial cell apoptosis via the mitochondrial pathway and impairs Paneth cell function; ClC-3 interacts with voltage-dependent anion channel 1 (VDAC1, a regulator of mitochondrial cytochrome c release) by co-immunoprecipitation; DSS treatment decreases the ClC-3/VDAC1 interaction; ClC-3-/- mice show increased susceptibility to experimental colitis. Clcn3-/- knockout mice, dextran sulfate sodium/TNBS colitis models, co-immunoprecipitation of ClC-3 with VDAC1, apoptosis assays, Paneth cell counting, antimicrobial peptide expression Gut High 24440986
2015 Three ClC-3 splice variants (ClC-3a, -3b, -3c) differ in subcellular targeting but mediate identical Cl-/H+ exchange: ClC-3a/b target to late endosomes/lysosomes via N-terminal dileucine-like motifs; ClC-3c targets to recycling endosomes via a novel N-terminal isoleucine-proline (IP) motif; all three produce equivalent outwardly rectifying Cl- currents with capacitive components. Identification of splice variants in mouse brain, immunofluorescence co-localization with compartment markers, site-directed mutagenesis of trafficking motifs, whole-cell patch-clamp The Journal of biological chemistry High 26342074
2016 Angiotensin II-induced Cl- current in vascular smooth muscle cells requires ClC-3 channel phosphorylation at threonine 532 by Rho-kinase 2 (ROCK2): ROCK2 co-immunoprecipitates with ClC-3 N- and C-termini; ROCK2 siRNA abolishes AngII-induced current; T532D phosphomimetic mutant potentiates, while T532A abolishes, AngII-induced current and VSMC migration; AngII-induced cerebrovascular remodeling is reduced in ClC-3 null mice. Co-immunoprecipitation, N/C-terminal truncation constructs, site-directed mutagenesis (T532D, T532A), ROCK2 siRNA, whole-cell patch-clamp, transwell migration assay, ClC-3 null mice British journal of pharmacology High 26562480
2017 ClC-4 sorting to endosomal compartments depends on its preferred heterodimerization with ClC-3: ClC-4 expressed alone is retained in ER; co-expression with ClC-3 splice variants redirects ClC-4 to late endosomes/lysosomes or recycling endosomes depending on which ClC-3 isoform is present; in Clcn3-/- astrocytes, ClC-4 is retained in the ER; high-resolution clear native PAGE shows ClC-3-ClC-4 heterodimers are more stable than ClC-4 homodimers. Heterologous co-expression, immunofluorescence co-localization, Clcn3-/- astrocytes, high-resolution clear native gel electrophoresis for oligomeric state analysis The Journal of biological chemistry High 28972156
2018 Detailed mechanistic analysis of ClC-3 Cl-/H+ exchange: the external gating glutamate E224 and central tyrosine anion gate Y572 act as anion barriers and interact to form a 'closed gate' conformation that maintains coupling; Y572S removal increases uncoupled anion current and impairs coupling; M531A mutation predicted to improve water-wire H+ supply improves exchange efficiency; external protons (pH 5.0) inhibit transport and shift gating charge; ClC-3 has lower transport efficiency but identical coupling ratio compared to ClC-5. Plasma membrane-localized ClC-3, whole-cell patch-clamp, pH manipulation, gating charge (Q) analysis, cytoplasmic alkalization rate measurement, multiple mutagenesis (E224A, Y572S, Y572F, M531A) The Journal of physiology High 29917234
2018 ClC-3 Cl-/H+ transporter regulates HER2 transcription in HER2-positive breast cancer cells through STAT3 signaling: ClC-3 siRNA knockdown in MDA-MB-453 cells markedly represses HER2 transcription and decreases STAT3 phosphorylation while increasing AKT phosphorylation. siRNA knockdown of ClC-3, qPCR and Western blot for HER2, phospho-AKT and phospho-STAT3 analysis, kinase inhibitors (AZD5363, everolimus, 5,15-DPP) Cancer science Medium 29949674
2018 ClC-3 promotes angiotensin II-induced NADPH oxidase activation and ROS production in endothelial cells by facilitating Nox2/p22phox expression and p38 MAPK-dependent phosphorylation and membrane translocation of p47phox/p67phox to form the Nox2 NADPH oxidase complex. ClC-3 knockdown/overexpression in HUVECs, NADPH oxidase activity assay, ROS measurement, p47phox/p67phox membrane fractionation, p38 MAPK inhibitor SB203580, Western blot for complex components Acta pharmacologica Sinica Medium 29977005
2021 De novo heterozygous missense variants and homozygous loss-of-function variants in CLCN3 cause neurodevelopmental disorders with GDD/ID and structural brain abnormalities; two missense variants (p.Ile607Thr and p.Thr570Ile) show increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH in Xenopus oocytes and mammalian cells, demonstrating gain-of-function alterations in Cl-/H+ exchange gating. Whole-exome sequencing, electrophysiological characterization of variants in Xenopus oocytes and mammalian cells, clinical neuroimaging (MRI) American journal of human genetics High 34186028
2012 VSMC migration requires ClC-3-dependent Ca2+-activated Cl- current (ICl.Ca): ICl.Ca is reduced ~50% in ClC-3 null VSMCs; the ClC-3-dependent component is activated by CaMKII (inhibited by KN-93) and inhibited by Ins(3,4,5,6)P4; ClC-3 null VSMCs show ~50% reduced migration in transwell assays; wild-type cell migration is reduced by niflumic acid, KN-93, or Ins(3,4,5,6)P4 but not in ClC-3 null cells. Whole-cell patch-clamp in WT and ClC-3 null VSMCs, CaMKII inhibitor, Ins(3,4,5,6)P4, transwell migration assay, Clcn3-/- genetic knockout Hypertension High 23150504
2008 Cardiac-specific inducible ClC-3 knockout eliminates native VSOAC currents in atrial and ventricular myocytes and causes myocardial hypertrophy and heart failure, establishing ClC-3 as the key molecular component of native VSOACs in mammalian heart and demonstrating a cardioprotective role. Inducible cardiac-specific Cre/lox ClC-3 knockout mice, echocardiography, patch-clamp of isolated cardiomyocytes, qRT-PCR and Western blot for ClC-3 loss Journal of molecular and cellular cardiology High 19615374
2022 HNRNPK is identified as a transcription factor that directly binds the CLCN3 promoter (binding motif 'GCGAGG', binding site -538/-248 bp) and drives CLCN3 transcription; HNRNPK knockdown suppresses CLCN3 promoter activity and mRNA/protein expression; reduced extracellular ClC-3 secretion from HNRNPK-silenced cells inhibits cancer-associated fibroblast (CAF) activation and TGF-β1 production. 5'-biotin-labeled promoter pulldown assay to identify HNRNPK, promoter activity reporter assays, shRNA knockdown, RNA-seq, xenograft mouse model, CAF isolation and functional assays International journal of biological sciences Medium 36439880

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signaling endosomes containing Nox1 and ClC-3. Circulation research 173 17673675
1999 A serine residue in ClC-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume. The Journal of general physiology 147 9874688
2001 Regulation of human CLC-3 channels by multifunctional Ca2+/calmodulin-dependent protein kinase. The Journal of biological chemistry 127 11274166
2006 Anion channels, including ClC-3, are required for normal neutrophil oxidative function, phagocytosis, and transendothelial migration. The Journal of biological chemistry 124 16522634
2002 CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis. Genes to cells : devoted to molecular & cellular mechanisms 122 12059962
2002 The ClC-3 chloride channel promotes acidification of lysosomes in CHO-K1 and Huh-7 cells. American journal of physiology. Cell physiology 114 11997263
2010 Molecular interaction and functional regulation of ClC-3 by Ca2+/calmodulin-dependent protein kinase II (CaMKII) in human malignant glioma. The Journal of biological chemistry 109 20139089
2000 Biophysical properties of ClC-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-K1 cells. The Journal of biological chemistry 109 10973952
2004 AP-3-dependent mechanisms control the targeting of a chloride channel (ClC-3) in neuronal and non-neuronal cells. The Journal of biological chemistry 98 15073168
2000 The role of ClC-3 in volume-activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition. The Journal of physiology 98 10747184
2008 ClC3 is a critical regulator of the cell cycle in normal and malignant glial cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 97 18784301
2002 ClC-3 is a fundamental molecular component of volume-sensitive outwardly rectifying Cl- channels and volume regulation in HeLa cells and Xenopus laevis oocytes. The Journal of biological chemistry 95 12183454
2002 Deficiency in ClC-3 chloride channels prevents rat aortic smooth muscle cell proliferation. Circulation research 93 12433844
2002 Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC-3 voltage-gated chloride channels. Brain research 90 12470859
2006 The ClC-3 Cl- channel in cell volume regulation, proliferation and apoptosis in vascular smooth muscle cells. Trends in pharmacological sciences 89 16697056
2001 Human ClC-3 is not the swelling-activated chloride channel involved in cell volume regulation. The Journal of biological chemistry 85 11278960
2004 Regulation of intracellular Cl- concentration through volume-regulated ClC-3 chloride channels in A10 vascular smooth muscle cells. The Journal of biological chemistry 84 15596438
2002 Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene. The Journal of physiology 83 12433961
2013 Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 23345219
2013 ClC-3 is an intracellular chloride/proton exchanger with large voltage-dependent nonlinear capacitance. ACS chemical neuroscience 75 23509947
2010 Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer research 75 21115901
2007 Overexpression of CLC-3 in HEK293T cells yields novel currents that are pH dependent. American journal of physiology. Cell physiology 75 17977943
1995 Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein. Genomics 71 7665160
2008 Suppression of ClC-3 channel expression reduces migration of nasopharyngeal carcinoma cells. Biochemical pharmacology 69 18359479
2002 ClC-3B, a novel ClC-3 splicing variant that interacts with EBP50 and facilitates expression of CFTR-regulated ORCC. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 11967229
2001 Functional inhibition of native volume-sensitive outwardly rectifying anion channels in muscle cells and Xenopus oocytes by anti-ClC-3 antibody. The Journal of physiology 69 11230516
2003 Functional effects of novel anti-ClC-3 antibodies on native volume-sensitive osmolyte and anion channels in cardiac and smooth muscle cells. American journal of physiology. Heart and circulatory physiology 68 12816749
2000 Expression and canalicular localization of two isoforms of the ClC-3 chloride channel from rat hepatocytes. American journal of physiology. Gastrointestinal and liver physiology 67 10915634
2006 CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons. Neuron 65 17046694
2004 Bcl-2-dependent modulation of swelling-activated Cl- current and ClC-3 expression in human prostate cancer epithelial cells. Cancer research 65 15256454
1998 The swelling-activated chloride channel ClC-2, the chloride channel ClC-3, and ClC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells. The Journal of clinical investigation 65 9449697
1996 Association of ClC-3 channel with Cl- transport by human nonpigmented ciliary epithelial cells. The Journal of membrane biology 65 8661780
2008 Silence of ClC-3 chloride channel inhibits cell proliferation and the cell cycle via G/S phase arrest in rat basilar arterial smooth muscle cells. Cell proliferation 64 18823498
2005 ClC-3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery. British journal of pharmacology 64 15723096
2004 ClC-3-independent, PKC-dependent activity of volume-sensitive Cl channel in mouse ventricular cardiomyocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 60 15319524
2010 Activation of swelling-activated chloride current by tumor necrosis factor-alpha requires ClC-3-dependent endosomal reactive oxygen production. The Journal of biological chemistry 58 20479003
2004 Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current. The Journal of physiology 58 14754994
2011 The ClC-3 chloride channels in cardiovascular disease. Acta pharmacologica Sinica 57 21602838
2008 Role of the vesicular chloride transporter ClC-3 in neuroendocrine tissue. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 18923035
2011 Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus. Nature neuroscience 55 21378974
2003 Fundamental role of ClC-3 in volume-sensitive Cl- channel function and cell volume regulation in AGS cells. American journal of physiology. Gastrointestinal and liver physiology 53 12842831
2015 Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. The Journal of biological chemistry 52 26342074
2009 The ClC-3 Cl-/H+ antiporter becomes uncoupled at low extracellular pH. The Journal of biological chemistry 51 19926787
2007 ClC-3 is required for LPA-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. American journal of physiology. Cell physiology 51 18077605
2014 CLC-3 channels in cancer (review). Oncology reports 50 25421907
2013 Discovery of bufadienolides as a novel class of ClC-3 chloride channel activators with antitumor activities. Journal of medicinal chemistry 50 23799775
2000 Molecular distribution of volume-regulated chloride channels (ClC-2 and ClC-3) in cardiac tissues. American journal of physiology. Heart and circulatory physiology 49 11045957
2007 ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment. Molecular cancer therapeutics 47 17363491
2014 ClC-3 chloride channel/antiporter defect contributes to inflammatory bowel disease in humans and mice. Gut 46 24440986
2009 Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. Cell metabolism 45 19808023
2008 ClC-3 and IClswell are required for normal neutrophil chemotaxis and shape change. The Journal of biological chemistry 44 18840613
2007 The ClC-3 chloride transport protein traffics through the plasma membrane via interaction of an N-terminal dileucine cluster with clathrin. The Journal of biological chemistry 44 17652080
2007 Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3. The Journal of biological chemistry 42 17908687
2006 ClC-3 chloride channel prevents apoptosis induced by thapsigargin in PC12 cells. Apoptosis : an international journal on programmed cell death 41 16520896
2014 The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3. Biomaterials 38 24743031
2011 ClC-3 chloride channel prevents apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells through mitochondria dependent pathway. Apoptosis : an international journal on programmed cell death 37 21373935
2010 ClC-3 chloride channels are essential for cell proliferation and cell cycle progression in nasopharyngeal carcinoma cells. Acta biochimica et biophysica Sinica 37 20539936
2008 Intracellular ClC-3 chloride channels promote bone resorption in vitro through organelle acidification in mouse osteoclasts. American journal of physiology. Cell physiology 37 18234851
2021 Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders. American journal of human genetics 36 34186028
2016 ClC-3 Chloride Channel Proteins Regulate the Cell Cycle by Up-regulating cyclin D1-CDK4/6 through Suppressing p21/p27 Expression in Nasopharyngeal Carcinoma Cells. Scientific reports 35 27451945
2009 Cardiac-specific, inducible ClC-3 gene deletion eliminates native volume-sensitive chloride channels and produces myocardial hypertrophy in adult mice. Journal of molecular and cellular cardiology 35 19615374
2013 Acid-sensitive outwardly rectifying (ASOR) anion channels in human epithelial cells are highly sensitive to temperature and independent of ClC-3. Pflugers Archiv : European journal of physiology 34 23708799
2014 Involvement of ClC-3 chloride/proton exchangers in controlling glutamatergic synaptic strength in cultured hippocampal neurons. Frontiers in cellular neuroscience 32 24904288
2013 The ClC-3 chloride channel associated with microtubules is a target of paclitaxel in its induced-apoptosis. Scientific reports 31 24026363
2005 ClC-3-independent sensitivity of apoptosis to Cl- channel blockers in mouse cardiomyocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 16037691
2004 Hyposmotic activation of ICl,swell in rabbit nonpigmented ciliary epithelial cells involves increased ClC-3 trafficking to the plasma membrane. Biochemistry and cell biology = Biochimie et biologie cellulaire 31 15674438
2016 Abrogating ClC-3 Inhibits LPS-induced Inflammation via Blocking the TLR4/NF-κB Pathway. Scientific reports 29 27363391
2013 ClC-3 deficiency prevents apoptosis induced by angiotensin II in endothelial progenitor cells via inhibition of NADPH oxidase. Apoptosis : an international journal on programmed cell death 29 23873092
2012 ClC-3 is a candidate of the channel proteins mediating acid-activated chloride currents in nasopharyngeal carcinoma cells. American journal of physiology. Cell physiology 29 22496242
2012 Cell cycle-dependent subcellular distribution of ClC-3 in HeLa cells. Histochemistry and cell biology 28 22371056
2011 Kinase activation of ClC-3 accelerates cytoplasmic condensation during mitotic cell rounding. American journal of physiology. Cell physiology 28 22049206
2001 Tissue-specific N-glycosylation of the ClC-3 chloride channel. Biochemical and biophysical research communications 28 11511107
2011 Ion-deficient environment induces the expression of basolateral chloride channel, ClC-3-like protein, in gill mitochondrion-rich cells for chloride uptake of the tilapia Oreochromis mossambicus. Physiological and biochemical zoology : PBZ 27 21091354
2010 Chloride channel ClC-3 in gills of the euryhaline teleost, Tetraodon nigroviridis: expression, localization and the possible role of chloride absorption. The Journal of experimental biology 27 20154183
2010 Chloride channel ClC-3 promotion of osteogenic differentiation through Runx2. Journal of cellular biochemistry 27 20506205
2008 An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC-3 function. Current biology : CB 27 18951024
2017 Suppression of CLC-3 chloride channel reduces the aggressiveness of glioma through inhibiting nuclear factor-κB pathway. Oncotarget 26 28969029
2005 Inhibition of swelling-activated Cl- currents by functional anti-ClC-3 antibody in native bovine non-pigmented ciliary epithelial cells. Investigative ophthalmology & visual science 25 15728552
2018 Modulation of ClC-3 gating and proton/anion exchange by internal and external protons and the anion selectivity filter. The Journal of physiology 24 29917234
2017 Activation of ClC-3 chloride channel by 17β-estradiol relies on the estrogen receptor α expression in breast cancer. Journal of cellular physiology 24 28419445
2017 Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments. The Journal of biological chemistry 24 28972156
2022 HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction. International journal of biological sciences 23 36439880
2019 Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 31606620
2018 Transcriptional repression of human epidermal growth factor receptor 2 by ClC-3 Cl- /H+ transporter inhibition in human breast cancer cells. Cancer science 23 29949674
2011 ClC-3 is a main component of background chloride channels activated under isotonic conditions by autocrine ATP in nasopharyngeal carcinoma cells. Journal of cellular physiology 23 21792908
1999 Single-cell RT-PCR demonstrates expression of voltage-dependent chloride channels (ClC-1, ClC-2 and ClC-3) in outer hair cells of rat cochlea. Brain research 23 10446329
2014 Swelling-activated Cl- currents and intracellular CLC-3 are involved in proliferation of human pulmonary artery smooth muscle cells. Journal of hypertension 22 24284495
2006 Single-channel properties of volume-sensitive Cl- channel in ClC-3-deficient cardiomyocytes. The Japanese journal of physiology 22 16441975
2004 ClC-3 expression in the cell cycle of nasopharyngeal carcinoma cells. Sheng li xue bao : [Acta physiologica Sinica] 22 15127135
2015 ClC-3 chloride channel modulates the proliferation and migration of osteosarcoma cells via AKT/GSK3β signaling pathway. International journal of clinical and experimental pathology 21 25973047
2018 ClC-3 promotes angiotensin II-induced reactive oxygen species production in endothelial cells by facilitating Nox2 NADPH oxidase complex formation. Acta pharmacologica Sinica 20 29977005
2007 Hypotonic activation of short ClC3 isoform is modulated by direct interaction between its cytosolic C-terminal tail and subcortical actin filaments. The Journal of biological chemistry 20 17442672
2016 Threonine532 phosphorylation in ClC-3 channels is required for angiotensin II-induced Cl(-) current and migration in cultured vascular smooth muscle cells. British journal of pharmacology 19 26562480
2016 ClC-3 Expression and Its Association with Hyperglycemia Induced HT22 Hippocampal Neuronal Cell Apoptosis. Journal of diabetes research 19 26925421
2014 A newly cloned ClC-3 isoform, ClC-3d, as well as ClC-3a mediates Cd-sensitive outwardly rectifying anion currents. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 24603049
2014 ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice. Apoptosis : an international journal on programmed cell death 19 25218423
2013 Deficiency of volume-regulated ClC-3 chloride channel attenuates cerebrovascular remodelling in DOCA-salt hypertension. Cardiovascular research 19 23786998
2012 Functional regulation of ClC-3 in the migration of vascular smooth muscle cells. Hypertension (Dallas, Tex. : 1979) 19 23150504
2012 CLC-3 chloride channels moderate long-term potentiation at Schaffer collateral-CA1 synapses. The Journal of physiology 19 23165767
2013 The ClC-3 chloride channel and osmoregulation in the European sea bass, Dicentrarchus labrax. Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology 18 23292336