Affinage

CLCN2

Chloride channel protein 2 · UniProt P51788

Length
898 aa
Mass
98.5 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 42 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

CLCN2 encodes ClC-2, a hyperpolarization-activated, inward-rectifying plasma-membrane Cl⁻ channel that sets the transmembrane chloride gradient and provides a background conductance controlling cellular excitability and epithelial ion transport (PMID:8816717, PMID:20357128). The channel is a double-barreled dimer whose voltage-dependent gating is driven primarily by intracellular anion occupancy of the pore rather than extracellular protonation, operating through a fast protopore gate centered on glutamate E207 and a coupled slow common gate involving C256, H811, and the CBS-2 domain (PMID:26666914, PMID:16469788, PMID:14724195). Gating and surface activity are tuned by a cytoplasmic D7–D8 inhibitory loop and an N-terminal 'ball' domain that also binds actin (PMID:9130703, PMID:11104687), by C-terminal CBS domains that bind ATP to favor closed states (PMID:23632988, PMID:18801843), and by phosphorylation: PKA activates the channel at defined C-terminal sites, while p34cdc2/cyclin B phosphorylation at Ser632 attenuates currents and triggers phosphorylation-dependent ubiquitination (PMID:15010473, PMID:11986377, PMID:12105212). Channel abundance is set by trafficking and proteostasis machinery including dynein-mediated retrograde transport, Hsp90 chaperoning, Nedd4-2/SGK-regulated membrane delivery, and CUL4-DDB1-CRBN E3 ligase-mediated proteasomal degradation (PMID:12601004, PMID:16049054, PMID:15358127, PMID:32466489). In glia, the auxiliary subunit GlialCAM directly binds ClC-2, stabilizes the open common gate, and, hierarchically downstream of MLC1, targets it to astrocytic junctions and endfeet (PMID:22405205, PMID:25185546, PMID:24647135). Physiologically, ClC-2 controls neuronal Cl⁻ homeostasis and excitability (PMID:20357128, PMID:20676104), supports retinal pigment epithelial and Sertoli cell environments at blood-tissue barriers (PMID:11250895), mediates basolateral Cl− exit for intestinal NaCl absorption (PMID:22079595, PMID:15057749), and sets the resting potential of adrenal glomerulosa cells (PMID:29403011, PMID:29403012). Loss-of-function CLCN2 mutations cause leukoencephalopathy with intramyelinic edema and retinal/testicular degeneration (PMID:23707145, PMID:33187987), whereas gain-of-function mutations depolarize glomerulosa cells and cause familial hyperaldosteronism type II (PMID:29403011, PMID:29403012, PMID:31727896).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1996 High

    Established that ClC-2 sets the neuronal chloride gradient that determines whether GABA signaling is inhibitory or excitatory, defining its physiological role in the nervous system.

    Evidence Adenoviral ClC-2 expression in primary dorsal root ganglion neurons with whole-cell electrophysiology

    PMID:8816717

    Open questions at the time
    • Did not resolve native channel gating mechanism
    • Overexpression system rather than endogenous regulation
  2. 1999 High

    Defined transcriptional control of CLCN2, showing Sp1/Sp3 drive its developmental (perinatal) expression in lung epithelium.

    Evidence Promoter-luciferase reporters, EMSA with supershift, and Sp1/Sp3 immunoblotting

    PMID:10198359

    Open questions at the time
    • Tissue-specific regulation outside lung not addressed
    • No link to channel function established
  3. 2000 High

    Identified the molecular basis of ClC-2 gating inhibition and its cytoskeletal regulation, locating an N-terminal 'ball' and a D7–D8 receptor loop and showing actin tonically inhibits the channel.

    Evidence Site-directed mutagenesis in Xenopus oocytes and GST-pulldown actin overlay/co-sedimentation assays

    PMID:11104687 PMID:9130703

    Open questions at the time
    • Structural basis of ball-and-chain inactivation not visualized
    • Physiological relevance of actin coupling in native cells unclear
  4. 2001 High

    Established essential in vivo roles at blood-tissue barriers, demonstrating ClC-2 loss causes retinal and testicular degeneration via failed ionic support of RPE and Sertoli cells.

    Evidence Clcn2 knockout mouse with histology, RPE current electrophysiology, and immunolocalization; ortholog loss-of-function in C. elegans

    PMID:11231150 PMID:11250895

    Open questions at the time
    • Cell-autonomous requirement not yet resolved
    • Mechanism linking conductance to tissue support indirect
  5. 2002 High

    Linked ClC-2 to cell-cycle-dependent regulation, showing M-phase kinase phosphorylation at Ser632 attenuates current and couples to ubiquitination, and confirmed it as the hyperpolarization-activated Cl− channel of acinar cells.

    Evidence In vitro phosphorylation, S632A mutagenesis, yeast two-hybrid for PP1, ubiquitination assays, and KO acinar cell patch clamp

    PMID:11976342 PMID:11986377 PMID:12105212

    Open questions at the time
    • E3 ligase responsible for M-phase ubiquitination not identified here
    • Physiological role of cell-cycle gating unclear
  6. 2003 High

    Identified trafficking control via dynein and the first human disease association, linking heterozygous loss-of-function to idiopathic generalized epilepsy.

    Evidence Dynein affinity pulldown/MS/reciprocal Co-IP with surface-expression assays; family genetics and mutant patch clamp in HEK cells

    PMID:12601004 PMID:12612585

    Open questions at the time
    • Epilepsy association later not reproduced in KO seizure-threshold tests
    • Dynein adaptor mediating ClC-2 recognition unknown
  7. 2004 High

    Resolved the dual fast/slow gating architecture, defined intracellular Cl− and PKA as activity regulators, and identified ClC-2 as the basolateral channel and pharmacological target (lubiprostone) for intestinal Cl− transport.

    Evidence C256 mutagenesis with Cd2+ pharmacology, phosphosite mutants, [Cl−]i-dependence in native colonocytes/Ussing chambers, and lubiprostone patch clamp with CFTR negative control

    PMID:14724195 PMID:15010473 PMID:15057749 PMID:15213059 PMID:15272009

    Open questions at the time
    • Direct binding site of lubiprostone not mapped
    • Coupling of intracellular Cl− sensing to gate motion not structurally defined
  8. 2005 High

    Showed Hsp90 chaperones ClC-2 to maintain its plasma-membrane pool and Cl−-dependent gating, adding a proteostasis layer to channel regulation.

    Evidence Reciprocal Co-IP/MS in HEK cells and brain, Hsp90 inhibitor pharmacology, surface-expression and patch-clamp assays

    PMID:16049054

    Open questions at the time
    • Whether Hsp90 acts at folding versus stability not distinguished
    • Co-chaperones not identified
  9. 2006 High

    Mapped the gate residues, identifying E207 as the protopore gate and H811/CBS-2 as the slow gate, and showed fast and slow gating are coupled in ClC-2 unlike ClC-0.

    Evidence H811A and E207V mutagenesis with resolution of fast/slow gating relaxations by patch clamp

    PMID:16469788

    Open questions at the time
    • Structural coupling mechanism between gates unresolved
    • Single-channel correlate not provided here
  10. 2008 High

    Defined the C-terminus as a bidirectional gating regulator, with partial truncation locking the channel closed and complete removal accelerating gating.

    Evidence Systematic C-terminal truncation mutants with whole-cell patch clamp gating analysis

    PMID:18801843

    Open questions at the time
    • Roles of individual CBS domains not fully separated
    • No structural model of C-terminal arrangement
  11. 2007 High

    Established ClC-2 as required for CNS ion/water homeostasis by showing knockout causes central white-matter vacuolation, while challenging the epilepsy link.

    Evidence Clcn2 knockout histology, auditory brainstem responses, and seizure-threshold testing

    PMID:17567819

    Open questions at the time
    • Glial versus neuronal site of action not resolved
    • Mechanism of intramyelinic edema undefined
  12. 2010 High

    Defined the dual neuronal role of ClC-2 as background conductance and chloride extruder, and revealed cell-type-specific control of perisomatic Cl− at basket-cell synapses.

    Evidence KO hippocampal slice patch clamp, field EPSP recordings, and cell-type-targeted synaptic recordings

    PMID:20357128 PMID:20676104

    Open questions at the time
    • Net excitability effect depends on cell context
    • Driving-force direction debated until clarified by dynamic-clamp work
  13. 2009 Medium

    Provided pharmacological and biophysical tools to dissect activation, identifying GaTx2 as a specific activation-gating inhibitor and PIKfyve as an SGK1-downstream regulator of surface availability.

    Evidence Venom peptide single-channel kinetics and specificity panel; oocyte voltage clamp with PIKfyve/SGK1 mutants

    PMID:19232516 PMID:19574231

    Open questions at the time
    • GaTx2 binding site on channel unmapped
    • PIKfyve link is indirect oocyte inference from a single lab
  14. 2011 High

    Established the intestinal transport function (basolateral NaCl/KCl absorption) and a non-conductive role in tight-junction integrity via caveolin/Rab5-dependent occludin trafficking.

    Evidence KO colon Ussing-chamber ion flux; Caco-2 siRNA/shRNA with proteomics, colocalization, and endocytosis/recycling assays; dynamic-clamp neuronal excitability test

    PMID:21956164 PMID:22049427 PMID:22079595

    Open questions at the time
    • Mechanism coupling channel to occludin trafficking unclear
    • Whether barrier role requires Cl− conduction not established
  15. 2012 High

    Identified GlialCAM as a direct auxiliary subunit that targets and activates ClC-2 at glial junctions, providing the molecular bridge to leukodystrophy.

    Evidence Co-IP, brain immunolocalization, patch clamp, and disease-mutant GLIALCAM analysis; JAK2 oocyte regulation

    PMID:22405205 PMID:22613974

    Open questions at the time
    • Functional consequence of GlialCAM activation for disease not yet tested
    • JAK2 effect is single-lab oocyte data
  16. 2013 High

    Confirmed CLCN2 loss-of-function causes human leukoencephalopathy with intramyelinic edema and defined ATP/CBS-domain control of common gating.

    Evidence Exome/Sanger sequencing with functional mutation analysis and human-brain immuno-EM; single-channel patch clamp with C-terminal truncation and kinetic modeling

    PMID:23632988 PMID:23707145

    Open questions at the time
    • Why intramyelinic edema arises mechanistically not resolved
    • Physiological ATP concentrations versus modeled effect not tied to disease
  17. 2014 High

    Defined the MLC1→GlialCAM→ClC-2 hierarchy in vivo and pinpointed the GlialCAM transmembrane domain acting on the common gate as the activation mechanism.

    Evidence Glialcam and Mlc1 KO mice with localization/electrophysiology; common-gate-deficient CLC mutants; systematic GlialCAM domain mutagenesis

    PMID:24647135 PMID:25185546 PMID:26033718

    Open questions at the time
    • Structural interface between GlialCAM TM and common gate not solved
    • SPAK/OSR1 negative regulation remains single-lab oocyte inference (PMID 25323061)
  18. 2015 High

    Established that anion occupancy of the pore, not extracellular protonation, drives ClC-2 voltage gating, revising the gating model.

    Evidence Whole-cell and inside-out patch clamp with systematic ionic substitutions, pH manipulation, and glutamate-gate mutagenesis

    PMID:26666914

    Open questions at the time
    • Structural site of anion sensing not defined
    • Relationship to physiological [Cl−]i changes not directly tied to disease
  19. 2017 High

    Showed how leukoencephalopathy mutations impair gating and stability and how GlialCAM/MLC1 rescue mutant ClC-2 at junctions, defining a tripartite complex.

    Evidence Patch clamp, surface biotinylation/turnover assays, and immunolocalization of mutant ClC-2 co-expressed with GlialCAM/MLC1

    PMID:28905383

    Open questions at the time
    • Whether rescue is therapeutically achievable in vivo not tested
    • Stoichiometry of the tripartite complex unknown
  20. 2018 High

    Identified gain-of-function CLCN2 mutations as a cause of familial hyperaldosteronism type II, establishing ClC-2 as the dominant resting Cl− conductance of adrenal glomerulosa cells.

    Evidence Two simultaneous exome studies with native glomerulosa patch clamp (KO controls) and aldosterone-synthase/aldosterone production assays

    PMID:29403011 PMID:29403012

    Open questions at the time
    • How modest open-probability increase scales to hormone output not fully quantified
    • Therapeutic blockade not tested here
  21. 2019 High

    Validated the aldosteronism mechanism in a knock-in mouse and confirmed ClC-2 sets glomerulosa resting potential for normal aldosterone production.

    Evidence Clcn2 R180Q knock-in with telemetry, plasma aldosterone/renin, adrenal calcium imaging, and Cyp11b2 analysis, complemented by KO

    PMID:31727896

    Open questions at the time
    • Sex-specific blood-pressure effect mechanism unexplained
    • Upstream triggers of channel opening in vivo unclear
  22. 2020 High

    Resolved the cellular sites of each disease and identified CUL4-DDB1-CRBN as the E3 ligase controlling ClC-2 degradation, integrating proteostasis with disease mutant behavior.

    Evidence Cell-type-specific conditional KO and Glialcam×Clcn2op genetic epistasis; Co-IP, ubiquitination, CRBN/cullin pharmacology in native cells with disease-mutant proteostasis analysis

    PMID:32466489 PMID:33187987

    Open questions at the time
    • Endogenous signals directing CRBN-mediated degradation unknown
    • GlialCAM-induced gating change shown irrelevant to leukodystrophy, leaving the disease mechanism partly open

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for how intracellular anion occupancy, CBS/ATP binding, and GlialCAM transmembrane contacts converge on the coupled fast and common gates remains unresolved.
  • No experimental structure of the gating or GlialCAM-bound complex
  • Mechanism of intramyelinic edema in leukodystrophy not mechanistically closed
  • Endogenous physiological triggers of trafficking/degradation control not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0008092 cytoskeletal protein binding 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 4
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2 R-HSA-382551 Transport of small molecules 2 R-HSA-392499 Metabolism of proteins 2
Partners
CRBNDYNC1H1GLIALCAMHSP90MLC1NEDD4LPPP1 (PP1)SGK1
Complex memberships
CUL4-DDB1-CRBN E3 ligase complexClC-2 homodimer (double-barreled)ClC-2–GlialCAM–MLC1 tripartite glial complexdynein retrograde motor complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ClC-2 activation by cell swelling, hyperpolarization, and acidic extracellular pH converges on a cytoplasmic loop between transmembrane domains D7 and D8 that acts as a gating inhibitor; mutations in this loop constitutively open the channel without altering pore properties, suggesting a 'ball-and-chain'-type inactivation mechanism where the N-terminus acts as the ball and this loop region as its receptor. Site-directed mutagenesis of ClC-2 expressed in Xenopus oocytes, electrophysiology The EMBO journal High 9130703
1996 Adenoviral expression of ClC-2 in cultured dorsal root ganglion neurons produced a large negative shift in the chloride equilibrium potential (ECl), attenuating GABA-mediated membrane depolarization and preventing GABAA receptor-mediated action potentials, establishing ClC-2 as a determinant of the transmembrane Cl− gradient that governs GABAergic inhibition versus excitation. Adenoviral gene transfer, mRNA/protein verification, whole-cell electrophysiology in primary neurons Neuron High 8816717
2001 Targeted disruption of Clcn2 in mice causes severe degeneration of the retina (photoreceptors lack normal outer segments, degenerate P10–P30) and testes (seminiferous tubules fail to develop lumina, primary spermatocytes die), while current across the retinal pigment epithelium is severely reduced; ClC-2 is normally expressed in Sertoli cells adjacent to germ cells, implicating it in controlling the ionic environment supporting cells at the blood-testis and blood-retina barriers. Clcn2 knockout mouse model, histology, electrophysiology (RPE current measurement), immunolocalization The EMBO journal High 11250895
2001 CLH-3, the C. elegans ortholog of ClC-2, is inactive in immature oocytes but is activated by meiotic maturation; RNAi knockdown of clh-3 leads to premature ovulatory contractions of gap junction-coupled gonadal sheath cells, placing CLH-3/ClC-2 as a regulator of ovulatory sheath cell contractile activity during meiotic maturation. Patch-clamp electrophysiology, RNAi (dsRNA interference), single-oocyte RT-PCR in C. elegans Current biology : CB High 11231150
2002 Clcn2 knockout mice completely lack hyperpolarization-activated Cl− currents in parotid acinar cells, identifying ClC-2 as the molecular basis of the hyperpolarization-activated Cl− channel in salivary acinar cells; however, salivary flow rate, electrolyte content, and regulatory volume decrease are unaffected in Clcn2−/− mice. Clcn2 knockout mouse, whole-cell patch clamp, in vivo salivary flow measurements, regulatory volume decrease assay The Journal of biological chemistry High 11976342
2003 Heterozygous loss-of-function mutations in CLCN2 (premature stop M200fsX231, splicing deletion del74-117, and missense G715E) are associated with idiopathic generalized epilepsy; M200fsX231 and del74-117 cause loss of function and are expected to lower the Cl− gradient for GABAergic inhibition, while G715E alters voltage-dependent gating. Family-based genetic analysis, heterologous expression of mutant channels in HEK cells, whole-cell patch clamp, confocal microscopy Nature genetics High 12612585
2004 SPI-0211 (lubiprostone) activates recombinant human ClC-2 Cl− currents in a concentration-dependent manner (EC50 ~17 nM) in stably transfected HEK-293 cells, independently of PKA, and has no effect on CFTR or on non-transfected cells; ClC-2 protein is expressed in the apical membrane of T84 cells and lubiprostone increases apical Cl− secretion. Whole-cell patch clamp of stably transfected HEK-293 cells (ClC-2 or CFTR), short-circuit current measurements across T84 monolayers, RT-PCR, Northern blot, in situ hybridization, immunolocalization American journal of physiology. Cell physiology High 15213059
2004 ClC-2 is located in the basolateral membrane of distal colon surface epithelium and its activity is directly regulated by intracellular Cl− concentration: increasing [Cl−]i shifts activation to more positive voltages, suggesting a cross-talk mechanism matching apical and basolateral fluxes in NaCl absorption. Ussing chamber (nystatin-perforated apical membrane), gramicidin D perforated-patch clamp of isolated colonocytes, whole-cell patch clamp of recombinant gpClC-2 in HEK cells, immunolocalization Gastroenterology High 15057749
2004 ClC-2 has a dual gating mechanism: a fast protopore gate and a slow common gate (analogous to ClC-0). Mutation of C256 (equivalent to C212 in ClC-0) produces constitutively open channels at all potentials, slows deactivation, reduces temperature dependence of deactivation, and reduces Cd2+ inhibition by 50%; Cd2+ accelerates deactivation of wild-type but not C256A, confirming C256 as part of the common gate. Site-directed mutagenesis, whole-cell patch clamp in mammalian cells, temperature-dependence analysis, pharmacological (Cd2+) experiments The Journal of physiology High 14724195
2000 The actin cytoskeleton normally exerts an inhibitory effect on ClC-2 activity; disruption of actin with cytochalasin or latrunculin enhances ClC-2 channel activity in Xenopus oocytes. The N-terminal inhibitory domain of ClC-2 binds actin directly via electrostatic interactions (inhibited at high NaCl), as shown by GST-fusion protein overlay and co-sedimentation assays. Xenopus oocyte expression, actin-disrupting agents (cytochalasin, latrunculin), GST-pulldown actin overlay and co-sedimentation assays The Biochemical journal High 11104687
2002 ClC-2 is phosphorylated by the M-phase-specific cyclin-dependent kinase p34cdc2/cyclin B at Ser632 in the C-terminus; this phosphorylation attenuates ClC-2 channel currents (but not S632A mutant), and ClC-2 is counter-regulated by protein phosphatase 1, which directly interacts with the ClC-2 C-terminus as shown by yeast two-hybrid. Additionally, ClC-2 is ubiquitinated at M phase in a phosphorylation-dependent manner (abolished by S632A mutation), leading to M-phase-specific expression. In vitro and cell-free phosphorylation assays, site-directed mutagenesis (S632A), Xenopus oocyte electrophysiology, yeast two-hybrid, ubiquitination assay, immunoblot of synchronized cells The Journal of physiology / The Journal of biological chemistry High 11986377 12105212
2003 ClC-2 interacts with the dynein retrograde motor complex: dynein heavy and intermediate chains bind ClC-2 in vitro (affinity matrix/mass spectrometry/Western blot), and dynein intermediate chain co-immunoprecipitates with ClC-2 from hippocampal membranes. Disruption of dynein motor function increases ClC-2 surface expression in COS7 cells, indicating dynein regulates ClC-2 trafficking to the plasma membrane. ClC-2 affinity matrix pulldown, mass spectrometry, Western blot, co-immunoprecipitation from hippocampal membranes, live cell imaging after dynein disruption, electrophysiology The Journal of biological chemistry High 12601004
2004 PKA phosphorylates ClC-2 at two consensus sites, RRAT655 and RGET691: either site suffices for PKA activation at neutral pH, but only RGET691 is sufficient at acidic pH; low extracellular pH activation of ClC-2 is PKA-dependent and requires RRAT655 (lost in RRAT655A mutant). PKA activation is also blocked by the PKA inhibitor mPKI. Site-directed mutagenesis of phosphorylation sites, whole-cell patch clamp of stably expressed hClC-2 in HEK-293 cells, pharmacological PKA activation/inhibition The Journal of biological chemistry High 15010473
2005 Hsp90 associates with ClC-2 (identified by co-immunoprecipitation and MS from HEK-293 cells; confirmed in mouse brain); pharmacological inhibition of Hsp90 (geldanamycin, radicicol) reduces ClC-2 plasma membrane abundance without affecting total ClC-2 protein, decreases ClC-2 current amplitude, impairs [Cl−]i-dependent rightward shift of fractional conductance, and slows activation kinetics. Heat shock has the opposite effect. Co-immunoprecipitation, mass spectrometry, whole-cell patch clamp, chemiluminescence surface expression assay American journal of physiology. Cell physiology High 16049054
2004 SGK1, SGK2, SGK3, and PKB (Akt) increase ClC-2 channel activity when co-expressed in Xenopus oocytes; Nedd4-2 decreases ClC-2 activity and plasma membrane abundance; SGKs reverse the Nedd4-2-mediated inhibition by increasing ClC-2 membrane abundance, suggesting SGK-mediated phosphorylation of Nedd4-2 prevents its interaction with ClC-2. Xenopus oocyte expression, dual electrode voltage clamp, chemiluminescence surface expression assay Biochemical and biophysical research communications Medium 15358127
2007 ClC-2 knockout mice develop widespread vacuolation of white matter in the brain and spinal cord (leukoencephalopathy) with fluid-filled spaces between myelin sheaths of the central but not peripheral nervous system, progressing with age; neuronal morphology is normal. Heterozygous loss produces no detectable phenotype, and neither heterozygous nor homozygous ClC-2 KO mice have lowered seizure thresholds. Clcn2 knockout mouse, histology, auditory brainstem response (conduction velocity), seizure threshold testing, human DNA sequencing + electrophysiology The Journal of neuroscience High 17567819
2009 GaTx2, a peptide toxin isolated from Leiurus quinquestriatus hebraeus venom, inhibits ClC-2 channels with a voltage-dependent apparent KD of ~20 pM by slowing activation (increasing latency to first opening ~8-fold) without affecting open channels, indicating it targets the channel's activation gating; it has no effect on other chloride channels or voltage-gated K+ channels. Peptide isolation from venom, whole-cell patch clamp, single-channel recordings, specificity testing against multiple channel types The Journal of biological chemistry High 19574231
2010 ClC-2 mediates chloride extrusion after high chloride load in CA1 pyramidal neurons; loss of ClC-2 dramatically increases input resistance and makes pyramidal cells more excitable, while also increasing GABAergic inhibition due to enhanced interneuron excitability—a dual role for ClC-2 in providing background conductance and in Cl− homeostasis. Clcn2 knockout mouse, whole-cell patch clamp, field EPSP recordings, GABAergic inhibition pharmacology in hippocampal slices The Journal of neuroscience High 20357128
2010 ClC-2 specifically modulates GABAA receptor-mediated synaptic inputs from parvalbumin-expressing basket cells onto hippocampal pyramidal neurons in a membrane voltage- and intracellular chloride-dependent manner, revealing cell-type-specific regulation of perisomatic intracellular Cl− homeostasis. Patch-clamp recordings in hippocampal slices from wild-type and Clcn2 knockout mice, specific targeting of basket cell synapses Nature neuroscience High 20676104
2012 GlialCAM is an auxiliary subunit of ClC-2: it directly binds ClC-2 (co-immunoprecipitation), targets ClC-2 to astrocyte-astrocyte junctions and astrocytic endfeet around blood vessels, increases ClC-2-mediated currents, and changes its functional properties. Disease-causing GLIALCAM mutations abolish targeting of the channel to cell junctions. Co-immunoprecipitation, immunolocalization in brain, whole-cell patch clamp in transfected cells, analysis of disease-causing GLIALCAM mutants Neuron High 22405205
2013 Homozygous or compound-heterozygous loss-of-function mutations in CLCN2 cause a leukoencephalopathy with intramyelinic edema in humans; ClC-2 is localized in all components of the panglial syncytium, enriched in astrocytic endfeet at the perivascular basal lamina, glia limitans, and ependymal cells, substantiating a role in brain ion and water homeostasis. Exome sequencing, Sanger sequencing, mRNA analysis, functional analysis of mutations, immunohistochemistry and electron microscopy of post-mortem human brain The Lancet. Neurology High 23707145
2013 ATP slows ClC-2 macroscopic activation and deactivation kinetics dose-dependently by binding to carboxy-terminal CBS domains (effect abolished by complete C-terminal truncation); single-channel recordings show ATP-bound channels enter long-lasting closed states. A 7-state model of common gating with altered voltage dependencies for ATP-bound states accounts for the data. Disease-associated variants (G715E, R577Q, R653T) accelerate common gating in the presence but not absence of ATP. Single-channel and whole-cell patch clamp of transfected mammalian cells, C-terminal truncation mutants, analysis of disease-associated variants, kinetic modeling Pflugers Archiv : European journal of physiology High 23632988
2014 GlialCAM is necessary for correct targeting of ClC-2 and MLC1 to specialized glial domains in vivo; in Glialcam knockout mice ClC-2 loses its biophysical modification specifically in oligodendrocytes; MLC1 is required for proper localization of GlialCAM and ClC-2 and for changing ClC-2 currents in vivo; ClC-2 is unnecessary for MLC1 and GlialCAM localization, revealing a hierarchical MLC1→GlialCAM→ClC-2 relationship in vivo. Glialcam and Mlc1 knockout mouse models, immunolocalization, whole-cell patch clamp in oligodendrocytes Nature communications High 24647135
2014 GlialCAM activates ClC-2 (and other CLC channels) by stabilizing the open configuration of the common (slow) gate: it slows deactivation of CLC-Ka/barttin and CLC-0 and increases CLC-0 currents by opening the common gate; common gate-deficient CLC-0 or ClC-2 mutants (E211V/H816A) are targeted to cell contacts by GlialCAM but show no functional change, demonstrating the common gate as the target of GlialCAM activation. Whole-cell patch clamp of transfected cells co-expressing GlialCAM with various CLC channels, common gate-deficient mutants, immunolocalization Biophysical journal High 25185546
2015 The extracellular domain of GlialCAM is necessary for junction targeting and for interactions with itself, MLC1, and ClC-2; the C-terminus of GlialCAM is required for junction targeting but not for biochemical interaction; the first three residues of the GlialCAM transmembrane segment are essential for ClC-2 current activation but not for targeting or biochemical interaction, pinpointing the transmembrane domain as the functional activation interface. Mutagenesis of GlialCAM domains, co-immunoprecipitation, whole-cell patch clamp, immunolocalization The Journal of physiology High 26033718
2015 Voltage-dependent gating of ClC-2 is driven primarily by intracellular anion occupancy of the pore rather than by protonation of the glutamate gate: gating is facilitated by permeant anions (Cl−, Br−, SCN−, I−) and occurs with poorly permeant anions (fluoride, glutamate), depends on pore occupancy, is strongly facilitated by multi-ion occupancy, and is present at intracellular pH 4.2; protonation by extracellular H+ plays a minor role. Whole-cell and inside-out patch clamp with systematic ionic substitutions, pH manipulation, mutagenesis of glutamate gate The Journal of general physiology High 26666914
2018 Gain-of-function heterozygous mutations in CLCN2 (including de novo p.Gly24Asp and recurrent p.Arg172Gln) cause familial hyperaldosteronism type II by increasing ClC-2 open probability at the glomerulosa resting membrane potential, depolarizing glomerulosa cells, and inducing aldosterone synthase expression; ClC-2 is identified as the predominant Cl− conductor setting the glomerulosa resting potential. Whole-exome sequencing, patch-clamp of adrenal glomerulosa cells from mouse adrenal slices (including Clcn2−/− controls), heterologous expression of mutant channels, aldosterone synthase expression and aldosterone production assays in adrenocortical cells Nature genetics High 29403011 29403012
2019 In Clcn2R180Q/+ knock-in mice (homologous to the most common FH-II mutation), adrenal Cyp11b2 expression and plasma aldosterone levels are elevated, adrenal slices show increased calcium oscillatory activity, and male mice have elevated blood pressure; conversely, Clcn2−/− mice require elevated renin to maintain normal aldosterone, confirming ClC-2's role in setting glomerulosa resting potential and normal aldosterone production. Knock-in mouse model, telemetry blood pressure, plasma aldosterone and renin measurement, adrenal slice calcium imaging, Cyp11b2 expression analysis Nature communications High 31727896
2020 Cell-type-specific deletion in mice shows that retinal degeneration requires loss of ClC-2 in retinal pigment epithelial cells, testicular degeneration requires loss in Sertoli cells, and leukodystrophy requires loss in both astrocytes and oligodendrocytes; the leukodystrophy of Glialcam−/− mice cannot be rescued by a Clcn2op/op mutation that mimics GlialCAM-induced channel opening, indicating GlialCAM-induced biophysical changes in ClC-2 are irrelevant for GLIALCAM-related leukodystrophy. Conditional (cell-type-specific) Clcn2 knockout mice, histology, genetic epistasis (Glialcam−/− × Clcn2op/op crosses) The Journal of biological chemistry High 33187987
2020 ClC-2 is subject to proteasomal degradation mediated by the CUL4-DDB1-CRBN E3 ubiquitin ligase complex; CRBN co-exists in the same complex with ClC-2 and promotes its polyubiquitination and degradation in heterologous and native (neuronal and testicular) cells; lenalidomide (CRBN-targeting drug) accelerates and MLN4924 (cullin E3 inhibitor) attenuates ClC-2 degradation; aldosteronism and leukodystrophy-associated mutants show opposite changes in ClC-2 proteostasis. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitors, lenalidomide and MLN4924 pharmacology, native neuronal and testicular cell validation, disease mutant analysis Cells High 32466489
2011 ClC-2 modulates tight junction barrier function via intracellular trafficking of the tight junction protein occludin: ClC-2 siRNA-treated Caco-2 cells show delayed TER development, diffuse occludin localization, and increased occludin colocalization with caveolin-1 and Rab5; ClC-2 shRNA cells show higher basal occludin endocytosis and reduced Rab5-dependent recycling, linking ClC-2 to caveolar trafficking of occludin. siRNA/shRNA knockdown in Caco-2 cells, proteomic analysis (LC-MS/MS), immunofluorescence colocalization, endocytosis/recycling assays, TER measurement American journal of physiology. Cell physiology High 21956164
2008 Partial truncation of the ClC-2 C-terminus locks the channel in a closed position and abolishes function; complete removal preserves function but accelerates both fast and slow gating. A single C-terminal domain suffices for normal slow gating, whereas both C-terminal domains regulate fast gating of individual protopores, demonstrating that cooperative slow gating does not require both domains and resides in other channel regions. C-terminal truncation mutants expressed in mammalian cells, whole-cell patch clamp, gating analysis The Journal of physiology High 18801843
2006 Mutation of the CBS-2 domain residue H811A in ClC-2 abolishes slow gating and affects fast gating, revealing that slow and fast gating processes are coupled in ClC-2; additional neutralization of pore glutamate E207V abolishes all gating, identifying E207 as the protopore gate. Unlike ClC-0 where fast and slow gates are independent, ClC-2 slow gating contributes to protopore gate operation. Site-directed mutagenesis (H811A, E207V), whole-cell patch clamp with resolution of fast and slow gating relaxations The Journal of physiology High 16469788
2004 Plasmodium infection of erythrocytes activates a ClC-2-type channel: infected erythrocytes from Clcn2+/+ but not Clcn2−/− mice show activation of volume-sensitive inwardly rectifying channels, and ClC-2 protein is confirmed in human erythrocytes; ClC-2 channel activity participates in the altered ionic permeability of Plasmodium-infected erythrocytes but is not required for parasite survival. Patch clamp of infected erythrocytes from Clcn2+/+ and Clcn2−/− mice, Western blot, FACS analysis, cell volume measurement The Journal of biological chemistry Medium 15272009
2011 ClC-2 reduces neuronal excitability by mediating chloride influx (outward current) under physiological driving force conditions rather than acting as a Cl− exit valve; virtual ClC-2 channels inserted via dynamic clamp into rat CA1 pyramidal cells reduce spiking independently of inhibitory synaptic transmission, demonstrating that the channel directly reduces excitability rather than maintaining Cl− homeostasis. Computer modeling, dynamic clamp insertion of virtual ClC-2 channels into rat CA1 pyramidal neurons, pharmacological ClC-2 block The Journal of neuroscience Medium 22049427
2012 JAK2 kinase downregulates ClC-2 activity when co-expressed in Xenopus oocytes by reducing ClC-2 protein insertion into (rather than accelerating retrieval from) the plasma membrane; constitutively active V617F-JAK2 produces the same effect, which is reversed by the JAK2 inhibitor AG490; inactive K882E-JAK2 has no effect. Xenopus oocyte expression, dual electrode voltage clamp, brefeldin A inhibition of insertion, JAK2 inhibitor AG490, chemiluminescence membrane abundance assay Cellular physiology and biochemistry Medium 22613974
2017 Leukoencephalopathy-causing CLCN2 mutations reduce ClC-2 functional expression by impairing gating and increasing plasma membrane turnover; GlialCAM rescues mutant ClC-2 (e.g., A500V) by modifying gating and stabilizing the channel at the plasma membrane, and this rescue requires ClC-2 to be localized at cell-cell junctions; MLC1 stabilizes wild-type but not mutant ClC-2 at the plasma membrane, confirming a GlialCAM/MLC1/ClC-2 tripartite complex. Electrophysiology (whole-cell patch clamp), biochemical turnover assays, surface biotinylation, immunolocalization, co-expression of GlialCAM and MLC1 with mutant ClC-2 The Journal of physiology High 28905383
1999 The ClC-2 gene promoter is GC-rich and TATA-box-free; a 67-bp GC box-containing sequence is critical for ClC-2 expression in fetal lung epithelial cells; Sp1 and Sp3 transcription factors bind this GC box (EMSA and antibody supershift), are perinatally downregulated in parallel with ClC-2, and thus mediate perinatal downregulation of ClC-2 in the lung. Promoter-luciferase reporter constructs, EMSA with antibody supershift, immunoblotting for Sp1/Sp3, serial promoter deletions The American journal of physiology High 10198359
2000 Human recombinant ClC-2 Cl− channels are activated by PKA (cAMP-dependent protein kinase), arachidonic acid, oleic acid, elaidic acid, ETYA, ibuprofen, and ebselen, and by reduced extracellular pH; arachidonic acid activation is independent of PKA or PKC. Whole-cell patch clamp of HEK-293 cells stably expressing human recombinant ClC-2, pharmacological agents, PKA inhibitor mPKI, PKC inhibitor staurosporine American journal of physiology. Cell physiology Medium 10898715
2009 PIKfyve (PIP5K3) stimulates ClC-2 activity in Xenopus oocytes; the stimulatory effect of PIKfyve requires an intact SGK1 consensus phosphorylation site (S318 of PIKfyve) and active SGK1, indicating PIKfyve acts downstream of SGK1 to regulate ClC-2 plasma membrane availability. Xenopus oocyte expression, dual electrode voltage clamp, kinase-inactive and phosphorylation-site mutants Biochemical and biophysical research communications Medium 19232516
2014 SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) negatively regulate ClC-2 activity in Xenopus oocytes when expressed in their active forms; the effect does not involve accelerated ClC-2 retrieval from the membrane (brefeldin A experiment), suggesting kinase-mediated inhibition of ClC-2 insertion. Xenopus oocyte expression, dual electrode voltage clamp, constitutively active and kinase-dead mutants of SPAK/OSR1, brefeldin A Kidney & blood pressure research Medium 25323061
2011 Clcn2−/− mouse distal colon shows severe defects in electroneutral NaCl and KCl absorption (not Cl− secretion) with ClC-2 localized to basolateral membranes of surface cells; Clcn2−/− mice show a compensatory ~3-fold increase in amiloride-sensitive (ENaC) short-circuit current. Clcn2 knockout mouse, Ussing chamber (ion flux measurements, short-circuit current), immunolocalization, immunoblot Gastroenterology High 22079595

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nature genetics 247 12612585
2001 Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption. The EMBO journal 245 11250895
1997 Molecular dissection of gating in the ClC-2 chloride channel. The EMBO journal 213 9130703
2004 SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. American journal of physiology. Cell physiology 183 15213059
2018 CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature genetics 179 29403011
1996 Alteration of GABAA receptor function following gene transfer of the CLC-2 chloride channel. Neuron 173 8816717
2013 Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. The Lancet. Neurology 155 23707145
2018 A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nature genetics 153 29403012
2007 Leukoencephalopathy upon disruption of the chloride channel ClC-2. The Journal of neuroscience : the official journal of the Society for Neuroscience 149 17567819
1998 Characteristics of rabbit ClC-2 current expressed in Xenopus oocytes and its contribution to volume regulation. The American journal of physiology 131 9486141
2012 GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron 123 22405205
2002 Distribution of ClC-2 chloride channel in rat and human epithelial tissues. American journal of physiology. Cell physiology 115 11880269
1998 Analysis of ClC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. Proceedings of the National Academy of Sciences of the United States of America 107 9520461
2014 Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nature communications 101 24647135
2002 Loss of hyperpolarization-activated Cl(-) current in salivary acinar cells from Clcn2 knockout mice. The Journal of biological chemistry 96 11976342
2000 Expression of the chloride channel ClC-2 in the murine small intestine epithelium. American journal of physiology. Cell physiology 93 11078693
2004 Functional evaluation of human ClC-2 chloride channel mutations associated with idiopathic generalized epilepsies. Physiological genomics 74 15252188
2004 Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte. The Journal of biological chemistry 71 15272009
2010 Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2. Nature neuroscience 70 20676104
2004 Basolateral ClC-2 chloride channels in surface colon epithelium: regulation by a direct effect of intracellular chloride. Gastroenterology 68 15057749
2004 The voltage-dependent ClC-2 chloride channel has a dual gating mechanism. The Journal of physiology 67 14724195
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
2019 A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma. European journal of endocrinology 64 31491746
2010 ClC-2 voltage-gated channels constitute part of the background conductance and assist chloride extrusion. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 20357128
2000 ClC-2 contributes to native chloride secretion by a human intestinal cell line, Caco-2. The Journal of biological chemistry 61 11096079
2004 Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. The Journal of biological chemistry 60 15007059
2000 PKA and arachidonic acid activation of human recombinant ClC-2 chloride channels. American journal of physiology. Cell physiology 60 10898715
2004 Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy. Neurology 57 15505175
2001 CLH-3, a ClC-2 anion channel ortholog activated during meiotic maturation in C. elegans oocytes. Current biology : CB 57 11231150
2004 ClC-2 chloride secretion mediates prostaglandin-induced recovery of barrier function in ischemia-injured porcine ileum. Gastroenterology 56 15362036
2002 ClC-2 in guinea pig colon: mRNA, immunolabeling, and functional evidence for surface epithelium localization. American journal of physiology. Gastrointestinal and liver physiology 56 12223361
2000 Splice variants of a ClC-2 chloride channel with differing functional characteristics. American journal of physiology. Cell physiology 54 11003600
2009 Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Human mutation 53 19191339
1999 Expression of the voltage-gated chloride channel ClC-2 in rod bipolar cells of the rat retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 10559393
1999 ClC-2 activation modulates regulatory volume decrease. The Journal of membrane biology 51 9929373
2011 Chloride channel ClC-2 modulates tight junction barrier function via intracellular trafficking of occludin. American journal of physiology. Cell physiology 50 21956164
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
2000 Chloride channel activity of ClC-2 is modified by the actin cytoskeleton. The Biochemical journal 48 11104687
2011 ClC-2 channels regulate neuronal excitability, not intracellular chloride levels. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 22049427
2008 Gating of human ClC-2 chloride channels and regulation by carboxy-terminal domains. The Journal of physiology 47 18801843
2010 ClC-2 regulates mucosal barrier function associated with structural changes to the villus and epithelial tight junction. American journal of physiology. Gastrointestinal and liver physiology 46 20489043
1998 Comparison of voltage-activated Cl- channels in rat parotid acinar cells with ClC-2 in a mammalian expression system. The Journal of membrane biology 46 9592073
2005 Quantitative analysis of the voltage-dependent gating of mouse parotid ClC-2 chloride channel. The Journal of general physiology 45 16286506
2001 ClC-2 chloride channels contribute to HTC cell volume homeostasis. American journal of physiology. Gastrointestinal and liver physiology 44 11171616
2001 Localization of ClC-2 Cl- channels in rabbit gastric mucosa. American journal of physiology. Cell physiology 44 11350755
2019 Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation. Nature communications 43 31727896
2003 Astrocytes from mouse brain slices express ClC-2-mediated Cl- currents regulated during development and after injury. Molecular and cellular neurosciences 43 12932434
2002 Phosphorylation and functional regulation of ClC-2 chloride channels expressed in Xenopus oocytes by M cyclin-dependent protein kinase. The Journal of physiology 42 11986377
2002 Effect of an N-terminus deletion on voltage-dependent gating of the ClC-2 chloride channel. The Journal of physiology 42 12381811
2004 Serum and glucocorticoid inducible kinases functionally regulate ClC-2 channels. Biochemical and biophysical research communications 41 15358127
2001 ClC-2 Cl- channels in human lung epithelia: activation by arachidonic acid, amidation, and acid-activated omeprazole. American journal of physiology. Cell physiology 41 11401826
2000 The chloride channel ClC-2 contributes to the inwardly rectifying Cl- conductance in cultured porcine choroid plexus epithelial cells. The Journal of physiology 40 10699077
2013 Methadone but not morphine inhibits lubiprostone-stimulated Cl- currents in T84 intestinal cells and recombinant human ClC-2, but not CFTR Cl- currents. Cell biochemistry and biophysics 39 22918821
2005 Association between Hsp90 and the ClC-2 chloride channel upregulates channel function. American journal of physiology. Cell physiology 39 16049054
1996 Identification of ClC-2-like chloride currents in pig pancreatic acinar cells. Pflugers Archiv : European journal of physiology 39 9019735
2003 Evidence for a functional interaction between the ClC-2 chloride channel and the retrograde motor dynein complex. The Journal of biological chemistry 38 12601004
2009 Isolation and characterization of a high affinity peptide inhibitor of ClC-2 chloride channels. The Journal of biological chemistry 37 19574231
2019 CLCN2-related leukoencephalopathy: a case report and review of the literature. BMC neurology 36 31291907
2007 Linkage and mutational analysis of CLCN2 in childhood absence epilepsy. Epilepsy research 36 17580110
2020 Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas. Journal of the Endocrine Society 35 33033789
2017 Chloride channel ClC- 2 enhances intestinal epithelial tight junction barrier function via regulation of caveolin-1 and caveolar trafficking of occludin. Experimental cell research 35 28161538
2012 Downregulation of ClC-2 by JAK2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 22613974
2012 Lubiprostone activates CFTR, but not ClC-2, via the prostaglandin receptor (EP(4)). Biochemical and biophysical research communications 34 22960173
2009 Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells. Journal of molecular and cellular cardiology 34 19376127
2006 Removal of gating in voltage-dependent ClC-2 chloride channel by point mutations affecting the pore and C-terminus CBS-2 domain. The Journal of physiology 34 16469788
2002 M phase-specific expression and phosphorylation-dependent ubiquitination of the ClC-2 channel. The Journal of biological chemistry 34 12105212
2017 Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl- channel function and trafficking. The Journal of physiology 33 28905383
2010 Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Investigative ophthalmology & visual science 32 20071672
2013 Regulation of ClC-2 gating by intracellular ATP. Pflugers Archiv : European journal of physiology 31 23632988
2017 Research and progress on ClC‑2 (Review). Molecular medicine reports 30 28534947
2014 Differentiation between human ClC-2 and CFTR Cl- channels with pharmacological agents. American journal of physiology. Cell physiology 30 25009109
1995 Molecular cloning and characterization of a novel truncated from (ClC-2 beta) of ClC-2 alpha (ClC-2G) in rabbit heart. FEBS letters 29 7498481
2020 Cellular basis of ClC-2 Cl- channel-related brain and testis pathologies. The Journal of biological chemistry 28 33187987
2014 GlialCAM, a CLC-2 Cl(-) channel subunit, activates the slow gate of CLC chloride channels. Biophysical journal 28 25185546
2011 Severe defects in absorptive ion transport in distal colons of mice that lack ClC-2 channels. Gastroenterology 28 22079595
2001 Regulation of ClC-2 chloride channels in T84 cells by TGF-alpha. American journal of physiology. Cell physiology 28 11350754
2015 Gating the glutamate gate of CLC-2 chloride channel by pore occupancy. The Journal of general physiology 26 26666914
2013 Chloride channel ClC-2 is a key factor in the development of DSS-induced murine colitis. Inflammatory bowel diseases 26 24030525
2013 Chloride channelopathies of ClC-2. International journal of molecular sciences 26 24378849
1997 Alternative mRNA splice variants of the rat ClC-2 chloride channel gene are expressed in lung: genomic sequence and organization of ClC-2. Nucleic acids research 26 9321672
2008 Clcn2 encodes the hyperpolarization-activated chloride channel in the ducts of mouse salivary glands. American journal of physiology. Gastrointestinal and liver physiology 25 18801913
2014 Regulation of ClC-2 activity by SPAK and OSR1. Kidney & blood pressure research 24 25323061
2009 PIKfyve-dependent regulation of the Cl- channel ClC-2. Biochemical and biophysical research communications 24 19232516
2000 Single-channel analysis of a ClC-2-like chloride conductance in cultured rat cortical astrocytes. FEBS letters 24 10940379
1999 Perinatal regulation of the ClC-2 chloride channel in lung is mediated by Sp1 and Sp3. The American journal of physiology 24 10198359
2013 Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia. American journal of physiology. Lung cellular and molecular physiology 23 23316067
2004 Sites of protein kinase A activation of the human ClC-2 Cl(-) channel. The Journal of biological chemistry 23 15010473
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
2015 ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target. Tissue barriers 22 26716076
1999 Low expression of the ClC-2 chloride channel during postnatal development: a mechanism for the paradoxical depolarizing action of GABA and glycine in the hippocampus. Proceedings. Biological sciences 22 10418163
2016 The CLC-2 Chloride Channel Modulates ECM Synthesis, Differentiation, and Migration of Human Conjunctival Fibroblasts via the PI3K/Akt Signaling Pathway. International journal of molecular sciences 21 27294913
2010 Analysis of CLCN2 as candidate gene for megalencephalic leukoencephalopathy with subcortical cysts. Genetic testing and molecular biomarkers 21 20187760
2005 Functional characterization of novel alternatively spliced ClC-2 chloride channel variants in the heart. The Journal of biological chemistry 21 15883157
2002 Inward-rectifying anion channels are expressed in the epithelial cells of choroid plexus isolated from ClC-2 'knock-out' mice. The Journal of physiology 21 11882672
1999 Keratinocyte growth factor stimulates CLC-2 expression in primary fetal rat distal lung epithelial cells. American journal of respiratory cell and molecular biology 21 10101018
2015 Structural determinants of interaction, trafficking and function in the ClC-2/MLC1 subunit GlialCAM involved in leukodystrophy. The Journal of physiology 20 26033718
2014 Identification and characterization of the zebrafish ClC-2 chloride channel orthologs. Pflugers Archiv : European journal of physiology 20 25236920
2020 CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy. Cells 19 32466489
2014 ClC-1 and ClC-2 form hetero-dimeric channels with novel protopore functions. Pflugers Archiv : European journal of physiology 19 24638271
2006 Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes. Neurogenetics 19 16932951

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