Affinage

SLC12A5

Solute carrier family 12 member 5 · UniProt Q9H2X9

Length
1139 aa
Mass
126.2 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC12A5 encodes KCC2, the principal neuron-specific K⁺-Cl⁻ cotransporter responsible for maintaining low intracellular Cl⁻ concentration required for hyperpolarizing GABAergic and glycinergic inhibition. KCC2 mediates isotonic Cl⁻ extrusion through a unique 15-amino-acid C-terminal ISO domain, and its surface expression and activity are dynamically regulated by opposing phosphorylation events—PKC-mediated Ser940 phosphorylation stabilizes membrane KCC2 while WNK-SPAK-dependent phosphorylation at Thr906/Thr1007 promotes internalization and Fbxl4-mediated proteasomal degradation—with NMDA receptor/Ca²⁺/PP1 signaling driving acute Ser940 dephosphorylation and KCC2 loss from the membrane (PMID:21532577, PMID:29176664, PMID:36973513, PMID:31396048). Beyond ion transport, KCC2 performs transport-independent functions through its C-terminal domain, regulating dendritic spine morphogenesis, AMPA receptor lateral diffusion via Rac1/cofilin-dependent actin remodeling, and cortical neuron survival during embryonic development (PMID:21878564, PMID:26631461, PMID:32064760). Recessive loss-of-function mutations in SLC12A5 cause epilepsy of infancy with migrating focal seizures, and missense variants impairing Cl⁻ extrusion or Ser940 phosphorylation are associated with idiopathic generalized epilepsy (PMID:26333769, PMID:24928908).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Establishing that KCC2 is a neuron-specific, postsynaptic protein co-localized with GABAA receptors resolved where Cl⁻ extrusion occurs relative to inhibitory synapses.

    Evidence Antibody-based immunohistochemistry and subcellular fractionation in rodent brain

    PMID:10212246

    Open questions at the time
    • Mechanism of postsynaptic targeting unknown
    • No functional transport data at this stage
  2. 2002 High

    Reconstitution of human KCC2 transport in oocytes demonstrated isotonic K⁺-Cl⁻ cotransport with defined kinetics and revealed phosphorylation-dependent regulation by calyculin-A sensitivity.

    Evidence 86Rb⁺ flux assay in Xenopus oocytes with pharmacological dissection

    PMID:12106695

    Open questions at the time
    • Specific phosphorylation sites unidentified
    • Mechanism distinguishing isotonic from swelling-activated transport unknown
  3. 2004 High

    Discovery that BDNF/TrkB signaling downregulates KCC2 mRNA and protein during epileptiform activity established activity-dependent transcriptional regulation as a mechanism for pathological loss of inhibition.

    Evidence Hippocampal slice electrophysiology with pathway inhibitor pharmacology and Western blot

    PMID:15140939

    Open questions at the time
    • Transcriptional cis-elements not yet defined
    • Rapid turnover mechanism uncharacterized
  4. 2006 High

    Identification of SDS-resistant KCC2 oligomers whose developmental increase parallels functional activation showed that oligomerization, not simply total expression, gates the GABA polarity switch.

    Evidence Non-reducing immunoblot, co-IP of tagged KCC2 variants, electrophysiology in LSO neurons

    PMID:17035525

    Open questions at the time
    • Stoichiometry and structural basis of oligomers undefined
    • Whether oligomerization is regulated by phosphorylation unknown
  5. 2009 High

    Mapping dual RE-1 elements in the Kcc2b promoter and demonstrating REST-dependent transcriptional repression explained how developmental de-repression drives KCC2 upregulation and the GABA switch.

    Evidence Promoter reporter assays, REST overexpression/inhibition, Cl⁻ measurement in cortical neurons

    PMID:19923298

    Open questions at the time
    • Epigenetic regulation of REST occupancy at KCC2 locus not explored
    • Contribution of Kcc2a isoform promoter not addressed
  6. 2011 High

    Three concurrent advances defined KCC2 post-translational regulation and non-canonical functions: (1) NMDAR/Ca²⁺/PP1-mediated Ser940 dephosphorylation causes acute KCC2 internalization; (2) KCC2 regulates AMPA receptor confinement in spines via cytoskeletal interaction independent of transport; (3) synaptic Zn²⁺ via GPR39 upregulates KCC2 surface expression.

    Evidence Phospho-specific antibodies, electrophysiology, single-particle tracking of GluR1, GPR39 KO mice, surface biotinylation

    PMID:21532577 PMID:21878564 PMID:21900570

    Open questions at the time
    • Structural basis of KCC2-cytoskeleton interaction unresolved
    • Relative contribution of Ser940 vs. other sites in vivo unknown
    • GPR39-KCC2 pathway not tested outside hippocampus
  7. 2012 High

    Identification of the 15-amino-acid ISO domain as uniquely required for isotonic (but not swelling-activated) transport explained why KCC2 alone among KCCs can maintain low neuronal Cl⁻ under physiological conditions.

    Evidence Chimeric KCC2-KCC4 constructs, Rb⁺ flux under isotonic/hypotonic conditions, EGABA measurement in hippocampal neurons

    PMID:22723714

    Open questions at the time
    • Molecular mechanism by which ISO domain enables isotonic transport unknown
    • No structural information for ISO domain
  8. 2014 High

    Functional characterization of human epilepsy-associated SLC12A5 variants (R952H, R1049C) showing impaired Cl⁻ extrusion and defective Ser940 phosphorylation established KCC2 phospho-regulation as a human disease mechanism.

    Evidence Gramicidin perforated patch-clamp and phospho-Ser940 Western blot of heterologously expressed variants

    PMID:24928908

    Open questions at the time
    • Mechanism by which R952H disrupts Ser940 phosphorylation not defined
    • In vivo confirmation in patient-derived neurons lacking
  9. 2015 High

    Convergent discoveries linked SLC12A5 to epilepsy of infancy with migrating focal seizures via recessive loss-of-function mutations, demonstrated Ser940 phosphorylation is essential for seizure survival in knock-in mice, and revealed transport-independent KCC2 roles in LTP through Rac1/cofilin/actin regulation.

    Evidence Whole-exome sequencing with functional validation, S940A knock-in mouse kainate SE model, KCC2 shRNA with cofilin phosphorylation assays

    PMID:25733865 PMID:26333769 PMID:26631461

    Open questions at the time
    • Genotype-phenotype spectrum for SLC12A5 mutations incompletely defined
    • Whether transport-independent synaptic plasticity role contributes to epilepsy phenotype unknown
  10. 2016 High

    Multiple regulatory axes were defined: KCC2 interacts with Task-3 channels to control resting K⁺ conductance independent of Cl⁻ transport, compound heterozygous EIMFS mutations produce additive partial loss-of-function in Cl⁻ extrusion, and TGF-β2 promotes KCC2 membrane trafficking via CREB/Rab11b.

    Evidence Co-IP and surface expression assays for Task-3, gramicidin patch-clamp of compound heterozygous mutant combinations, TGF-β2 signaling dissection with shRNA

    PMID:27436767 PMID:27505893 PMID:31269453

    Open questions at the time
    • Task-3–KCC2 interaction domain not mapped
    • Whether TGF-β2/Rab11b pathway operates in vivo during development untested
  11. 2017 High

    A comprehensive regulatory framework emerged: WNK1-dependent phosphorylation at Thr906/Thr1007 was shown to control KCC2 membrane confinement downstream of GABAAR Cl⁻ sensing, APP was identified as a stabilizer protecting KCC2 from ubiquitination, GABAB receptors were found to negatively regulate KCC2 surface levels, and NEM activation was mechanistically resolved through Thr1007 dephosphorylation via WNK-SPAK inhibition.

    Evidence Single-particle tracking, phospho-Western blots, co-IP from native tissue, App KO rescue experiments, mutagenesis of Thr1007

    PMID:28054918 PMID:28450542 PMID:29092909 PMID:29176664

    Open questions at the time
    • Integration of Ser940 and Thr906/1007 phosphorylation in a unified kinase/phosphatase signaling model incomplete
    • Structural basis of APP-KCC2 interaction unknown
  12. 2019 High

    Knock-in mice with non-phosphorylatable (S940A) or constitutively dephosphorylated (T906A/T1007A) KCC2 showed that timing of the developmental EGABA shift is controlled by these phosphorylation events and that perturbation causes lasting behavioral deficits.

    Evidence S940A and T906A/T1007A knock-in mice, in vivo developmental EGABA profiling, behavioral testing

    PMID:31396048

    Open questions at the time
    • Which neuron populations are most sensitive to altered phosphorylation timing unclear
    • Whether behavioral phenotypes reflect transport-dependent or -independent functions unknown
  13. 2020 High

    Demonstrating that KCC2's C-terminal domain prevents apoptosis of upper-layer cortical neurons via cytoskeletal interactions—independent of ion transport—established a developmental survival function for KCC2 beyond Cl⁻ homeostasis.

    Evidence Conditional KCC2 KO with in utero electroporation of transport-dead and CTD mutant (R952H) constructs

    PMID:32064760

    Open questions at the time
    • Downstream effectors of CTD-mediated anti-apoptotic signaling not identified
    • Whether this function is relevant postnatally unknown
  14. 2021 High

    Cryo-EM structures of KCC2 provided the first atomic-resolution framework for understanding ion coordination and phosphorylation-dependent conformational regulation, while identification of gephyrin as a KCC2 scaffold at GABAergic synapses explained how KCC2 is positioned for local Cl⁻ extrusion.

    Evidence Cryo-EM of mouse KCC2, co-IP from rat neocortex for gephyrin-KCC2, surface expression and Cl⁻ extrusion assays upon gephyrin loss

    PMID:33597714 PMID:34810232

    Open questions at the time
    • No structure of KCC2 in complex with regulatory partners
    • Gephyrin-KCC2 binding interface not mapped
  15. 2023 High

    Identification of Fbxl4 as a phospho-Thr1007-dependent E3 ligase for KCC2 proteasomal degradation during anesthesia recovery, and validation of direct small-molecule KCC2 activators that terminate benzodiazepine-resistant status epilepticus, opened translational avenues for pharmacological KCC2 modulation.

    Evidence Co-IP of KCC2-Fbxl4, in vivo anesthesia model, direct binding assay for small molecules, SE mouse model

    PMID:36889319 PMID:36973513

    Open questions at the time
    • Drug selectivity over other KCCs and cation-chloride cotransporters not fully characterized
    • Whether Fbxl4-mediated degradation operates in other pathological contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic mechanism by which the ISO domain enables isotonic transport, how transport-dependent and -independent functions are coordinated in vivo, the structural basis of KCC2 interactions with its regulatory partners (gephyrin, APP, 4.1N), and whether direct KCC2 activators can be developed into therapeutics for epilepsy and spinal cord injury.
  • No full-length KCC2 structure in complex with regulatory partners
  • Transport-independent signaling pathways downstream of CTD incompletely mapped
  • Clinical translation of KCC2-activating compounds not yet demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 GO:0005215 transporter activity 1
Partners
APPCBLBCKBFBXL4GPHNKCNK9MYLIPWNK1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KCC2 is an ~140-kDa glycoprotein exclusively expressed in the CNS, localized postsynaptically at neuronal somata and dendrites (absent from axons and glia), and co-localizes with GABAA receptor β2/β3 subunits at the plasma membrane of cerebellar granule cells, consistent with its role as a postsynaptic Cl- extrusion pathway. Polyclonal antibody development, immunohistochemistry, subcellular fractionation, co-localization with GABAA receptor subunits The Journal of biological chemistry High 10212246
2002 Human KCC2 (SLC12A5) expressed in Xenopus oocytes mediates Cl--dependent 86Rb+ uptake under isotonic conditions and is further activated ~20-fold by hypotonic swelling; this activation is blocked by the phosphatase inhibitor calyculin-A, indicating phosphorylation-dependent regulation. Km values for K+ and Cl- are ~9.3 mM and ~6.8 mM respectively under isotonic conditions. Xenopus oocyte expression system, 86Rb+ flux assay, pharmacological inhibition with calyculin-A, kinetic analysis Brain research. Molecular brain research High 12106695
2004 Sustained interictal-like activity in hippocampal slices downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons via endogenous BDNF acting on TrkB, with downstream signaling through Shc/FRS-2 and PLCγ-CREB cascades, reducing neuronal Cl- extrusion capacity. Plasmalemmal KCC2 has a very high turnover rate (tens of minutes). Hippocampal slice electrophysiology, pharmacological blockade of TrkB/PLCγ/Shc pathways, Western blot, mRNA quantification The Journal of neuroscience High 15140939
2005 Brain-type creatine kinase (CKB) physically interacts with KCC2 and activates its Cl--extruding function; dominant-negative CKB or pharmacological CK inhibition (DNFB) shifts the glycine reversal potential in a depolarizing direction in KCC2-expressing HEK293 cells and in primary cortical neurons. Gramicidin-perforated patch-clamp, HEK293 co-transfection, dominant-negative CKB overexpression, pharmacological CK inhibition Journal of neurochemistry Medium 16336223
2006 KCC2 forms SDS-resistant, sulfhydryl-sensitive oligomers (dimers, trimers, tetramers) in mature brain; the developmental increase in the oligomer/monomer ratio correlates with KCC2 functional activation and the shift to hyperpolarizing GABA responses, independent of increased total protein expression. Immunoblot under non-reducing/reducing conditions, co-immunoprecipitation of HA- and His-tagged KCC2 in HEK293 cells, confocal and electron microscopy, electrophysiology in LSO neurons The Journal of neuroscience High 17035525
2008 The RCC1 domain of PAM (Protein Associated with Myc) binds to the C-terminus of KCC2, as shown by yeast two-hybrid, GST pull-down, and co-immunoprecipitation in HEK293 cells; RCC1/PAM co-expression increases KCC2-mediated 86Rb/K+ flux, and a point mutation in the KCC2 C-terminus that abolishes PAM binding also eliminates N-ethylmaleimide (NEM)-induced KCC2 activation. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, 86Rb uptake assay, site-directed mutagenesis Cellular physiology and biochemistry High 18769030
2009 Two RE-1 sites in the 5' regulatory region of Kcc2b, recognized by the transcriptional repressor REST, act in concert to suppress Kcc2b transcription; inhibition of REST upregulates KCC2 protein and lowers intraneuronal Cl-, accelerating the developmental GABA switch, while REST overexpression delays it. BDNF-dependent upregulation of KCC2 requires the dual RE-1 site. Promoter reporter assays, REST inhibition/overexpression, KCC2 protein Western blot, intraneuronal Cl- measurement in cortical neurons The Journal of neuroscience High 19923298
2010 Premature overexpression of KCC2 in mouse embryos impairs neural tube and neural crest development through ion transport-independent mechanisms; a transport-inactive N-terminal-deleted KCC2 variant phenocopies full-length KCC2 overexpression, whereas a KCC2 mutant unable to bind the cytoskeletal protein 4.1N does not, implicating KCC2-4.1N interaction in cytoskeletal regulation during neuronal development. Transgenic mouse overexpression, neural-specific promoter, comparison of transport-dead vs. 4.1N-binding mutant variants, cytoplasmic 4.1N/actin distribution analysis The European journal of neuroscience High 20529123
2011 NMDA receptor activation and Ca2+ influx cause dephosphorylation of KCC2 at Ser940 via protein phosphatase 1 (PP1), leading to loss of KCC2 surface expression and impaired Cl- extrusion for >20 min in dissociated rat neurons; blocking Ser940 dephosphorylation preserves hyperpolarizing GABAergic inhibition. Phospho-specific Western blot (pSer940), pharmacological NMDA receptor activation, PP1 inhibitors, electrophysiology (EGABA measurement) in dissociated rat neurons Nature neuroscience High 21532577
2011 KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines through interaction with the actin cytoskeleton (not via ion transport); KCC2 knockdown reduces GluR1-containing AMPA receptor aggregation and increases GluR1 lateral diffusion specifically within spines, an effect mimicked by a dominant-negative cytoskeleton-interaction mutant but not by pharmacological KCC2 transport blockade. KCC2 siRNA knockdown, dominant-negative KCC2 (cytoskeleton interaction mutant), single-particle tracking of GluR1, electrophysiology (mEPSC), co-immunoprecipitation Proceedings of the National Academy of Sciences High 21878564
2011 Synaptic Zn2+ released from mossy fibers activates the metabotropic Zn2+ receptor mZnR/GPR39 (identified as GPR39 by knockout), triggering a Gαq/PLCβ/ERK signaling cascade that upregulates KCC2 surface expression and Cl- transport activity, producing a hyperpolarizing shift in EGABA in hippocampal neurons. GPR39 knockout mice, Zn2+ transporter-3 knockout mice, Cl- imaging, electrophysiology (EGABA), surface biotinylation, mossy fiber stimulation The Journal of neuroscience High 21900570
2012 A 15 amino-acid region near the C-terminus of KCC2 (the ISO domain), unique to KCC2 among KCC family members, is required for isotonic K+-Cl- cotransport but not for swelling-activated transport; chimeric KCC2-KCC4 constructs lacking the ISO domain abolish hyperpolarizing GABA responses in hippocampal neurons without eliminating swelling-activated transport. Chimeric KCC2-KCC4 constructs, gramicidin perforated patch-clamp (EGABA measurement) in cultured hippocampal neurons, isotonic vs. hypotonic Rb+ flux The Journal of neuroscience High 22723714
2015 In kainate-induced status epilepticus (SE), Ser940 of KCC2 is dephosphorylated, causing KCC2 internalization; S940A knock-in mice show lethality within 30 min of kainate-induced SE and exhibit selective deficits in KCC2 activity after glutamate exposure that cannot be rescued by phosphorylation-enhancing agents, demonstrating that S940 phosphorylation is critical for KCC2 activity potentiation during seizures. S940A knock-in mice, kainate SE model, phospho-specific Western blot, neuronal Cl- extrusion assays, pharmacological rescue experiments Proceedings of the National Academy of Sciences High 25733865
2015 Recessive loss-of-function mutations in SLC12A5 cause epilepsy of infancy with migrating focal seizures (EIMFS); the identified mutations reduce KCC2 surface expression, impair protein glycosylation, and decrease Cl- extrusion capacity, leading to impaired synaptic inhibition. Whole-exome sequencing, surface biotinylation assay, gramicidin perforated patch-clamp Cl- extrusion assay, glycosylation analysis in patient-derived and heterologous expression systems Nature communications High 26333769
2015 KCC2 suppression in rat hippocampal neurons prevents activity-driven AMPA receptor membrane delivery and long-term potentiation (LTP) via increased Rac1/PAK/LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines; this effect is independent of KCC2 transport function. KCC2 shRNA knockdown, LTP induction, AMPA receptor surface expression assay, cofilin phosphorylation Western blot, pharmacological Rac1 inhibition The Journal of neuroscience High 26631461
2016 KCC2 interacts with and is required for plasma membrane expression of Task-3 (KCNK9) leak K+ channels; KCC2 knockdown reduces Task-3 surface expression, depolarizes resting membrane potential, and increases neuronal excitability through altered K+ conductance, not solely through changes in Cl- homeostasis. Co-immunoprecipitation, surface expression assay, KCC2 shRNA knockdown in rat dentate gyrus, electrophysiology (resting membrane potential, excitability), in vivo recording Cell reports High 31269453
2016 Graded biallelic SLC12A5 mutations causing EIMFS produce differentially impaired Cl- extrusion (strongly suppressed for E50_Q93del and M415V, mildly for A191V and S323P) without affecting surface expression; compound heterozygous expression in cells produces intermediate intracellular Cl- levels, demonstrating additive partial loss-of-function. Gramicidin perforated patch-clamp, surface expression analysis, heterologous co-expression of compound heterozygous mutant pairs Scientific reports High 27436767
2016 TGF-β2 promotes KCC2 membrane trafficking and surface expression through a CREB/Rab11b signaling pathway; TGF-β2 increases KCC2-Rab11b co-localization and interaction, and loss of CREB1 or Rab11b function suppresses TGF-β2-dependent KCC2 surface expression and Cl- extrusion in hippocampal neurons. Surface biotinylation, co-immunoprecipitation, STED microscopy, shRNA knockdown of CREB1 and Rab11b, Cl- extrusion assay in primary hippocampal neurons Journal of cell science High 27505893
2017 APP physically interacts with KCC2, limits tyrosine phosphorylation and ubiquitination of KCC2, and thereby prevents its degradation; APP deficiency reduces total and membrane KCC2 levels, depolarizes EGABA, and impairs GABAergic inhibition in hippocampal neurons; restoring KCC2 rescues these deficits. Co-immunoprecipitation, Western blot for KCC2 levels/phosphorylation/ubiquitination, electrophysiology (EGABA, IPSC), KCC2 rescue by lentiviral expression in App KO neurons eLife High 28054918
2017 GABAB receptors physically associate with KCC2 and their activation decreases KCC2 surface expression and function; this reduces intracellular Cl- extrusion, providing a crosstalk mechanism between metabotropic and ionotropic GABA receptor systems in hippocampal neurons. Co-immunoprecipitation from hippocampal tissue, surface biotinylation, electrophysiology (EGABA), pharmacological GABABR agonist/antagonist application The Journal of neuroscience High 28450542
2017 GABAAR-mediated inhibition confines KCC2 to the plasma membrane via a Cl--dependent mechanism; reduced GABAAR activity increases KCC2 lateral diffusion and endocytosis. This regulation is mediated by the Cl--sensing kinase WNK1, which phosphorylates KCC2 at Thr906 and Thr1007 to regulate its membrane stability. Single-particle tracking, surface biotinylation, phospho-specific Western blot, WNK1 pharmacological inhibition/genetic manipulation, GABAAR agonist/antagonist in mature hippocampal neurons Nature communications High 29176664
2017 N-ethylmaleimide (NEM) increases KCC2 activity by increasing Ser940 phosphorylation and decreasing Thr1007 phosphorylation; the latter is mediated by inhibition of WNK-SPAK kinase signaling. Mutagenesis shows that Thr1007 dephosphorylation is the primary mechanism by which NEM enhances KCC2 surface expression and activity. Phospho-specific Western blot (pSer940, pThr1007, pSPAK), surface biotinylation, T1007A mutagenesis, electrophysiology in neurons The Journal of biological chemistry High 29092909
2018 KCC2 agonism in spinal inhibitory interneurons restores stepping ability in mice with spinal cord injury; selective expression of KCC2 or hyperpolarizing DREADDs specifically in inhibitory interneurons between staggered spinal lesions transforms dysfunctional spinal circuits into functional relay circuits for brain-derived commands. Small-molecule screen, viral KCC2 expression, DREADD-mediated hyperpolarization, behavioral locomotion assessment, staggered hemisection mouse model Cell High 30033363
2018 BDNF enhances KCC2 ubiquitination in spinal dorsal horn via the E3 ubiquitin ligase Cbl-b, promoting KCC2 degradation; KCC2-Cbl-b interaction is shown by co-immunoprecipitation, and Cbl-b knockdown decreases KCC2 ubiquitination and attenuates BDNF-induced pain hypersensitivity; spared nerve injury increases KCC2 ubiquitination via TrkB receptor activation. Co-immunoprecipitation, ubiquitination assay, Cbl-b siRNA knockdown, TrkB inhibition, behavioral pain assays European journal of pharmacology High 34048740
2019 KCC2 function is regulated by phosphorylation: preventing phosphorylation at Ser940 (S940A knock-in) delays the developmental EGABA shift, whereas preventing phosphorylation at Thr906/Thr1007 (T906A/T1007A knock-in) accelerates it; abnormal timing of these phosphorylation events causes long-term deficits in social behavior and memory retention in adult mice. S940A and T906A/T1007A knock-in mice, in vivo EGABA developmental profiling, behavioral assays (social behavior, memory) Frontiers in molecular neuroscience High 31396048
2020 Loss of non-canonical, ion transport-independent KCC2 functions (mediated via the C-terminal domain, CTD) promotes apoptosis of late-born upper-layer cortical projection neurons during embryonic brain development; transport-dead KCC2 constructs retaining the CTD prevent apoptosis, whereas a CTD missense mutant (R952H) that disrupts cytoskeletal interactions fails to do so. Conditional KCC2 knockout, in utero electroporation of transport-dead and CTD mutant constructs, apoptosis quantification in embryonic neocortex EMBO reports High 32064760
2021 Cryo-EM structures of human NKCC1 and mouse KCC2 reveal the structural basis for ion transport and phosphorylation-dependent regulation; computational and functional analysis identifies essential residues for ion transport and proposes mechanisms by which phosphorylation controls transporter activity. Cryo-electron microscopy, computational analysis, functional characterization (ion transport assays) Communications biology High 33597714
2021 Gephyrin, the main scaffolding protein at GABAergic synapses, interacts with KCC2 (confirmed by co-immunoprecipitation from rat neocortex), stabilizes plasmalemmal KCC2, and promotes its clustering near GABAergic synapses; loss of gephyrin reduces KCC2 membrane expression and impairs KCC2-mediated Cl- extrusion. Proteomics (KCC2 interactome), co-immunoprecipitation from rat neocortex, immunofluorescence, surface expression assay, electrophysiology (Cl- extrusion) in hippocampal neurons The Journal of neuroscience High 34810232
2023 Ubiquitin-proteasomal degradation of KCC2, driven by the ubiquitin ligase Fbxl4, in the ventral posteromedial thalamic nucleus (VPM) is a common mechanism for brain recovery of consciousness from anesthesia; KCC2 downregulation causes GABAA receptor-mediated disinhibition enabling VPM neuron excitability recovery. Phosphorylation of KCC2 at Thr1007 promotes KCC2-Fbxl4 interaction. In vivo mouse anesthesia model, Fbxl4 manipulation, phospho-KCC2 Thr1007 assay, co-immunoprecipitation of KCC2-Fbxl4, proteasome inhibition, Ca2+ imaging, electrophysiology Nature neuroscience High 36973513
2023 Small molecules that directly bind to and activate KCC2 reduce neuronal Cl- accumulation and excitability; direct KCC2 activation prevents development of and terminates ongoing benzodiazepine-resistant status epilepticus and reduces associated neuronal cell death in mice. Small-molecule screen, direct binding assay, neuronal Cl- measurement, in vivo SE model, behavioral and neuropathological readouts Cell reports. Medicine High 36889319
2014 Two human SLC12A5 missense variants (R952H and R1049C) found in idiopathic generalized epilepsy exhibit significantly impaired Cl- extrusion capacity, less hyperpolarized glycine equilibrium potentials, and impaired stimulatory phosphorylation at Ser940, demonstrating that genetically encoded impairment of KCC2 phospho-regulation is a disease mechanism. Gramicidin perforated patch-clamp, phospho-Ser940 Western blot, heterologous expression of variants, Cl- extrusion assay EMBO reports High 24928908

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2. The Journal of neuroscience : the official journal of the Society for Neuroscience 399 15140939
2004 Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. The Journal of physiology 321 15528236
2011 NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nature neuroscience 242 21532577
2004 Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride. The Journal of comparative neurology 225 14648690
2012 Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 213 22705273
2006 Oligomerization of KCC2 correlates with development of inhibitory neurotransmission. The Journal of neuroscience : the official journal of the Society for Neuroscience 197 17035525
1999 The neuron-specific K-Cl cotransporter, KCC2. Antibody development and initial characterization of the protein. The Journal of biological chemistry 190 10212246
2013 Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends in neurosciences 172 24139641
2014 GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 149 25066727
2018 Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations. Cell 148 30033363
2014 Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO reports 141 24928908
2015 Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nature communications 128 26333769
2003 Developmental up-regulation of KCC2 in the absence of GABAergic and glutamatergic transmission. The European journal of neuroscience 119 14686894
2011 Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 21900570
2005 Early expression of KCC2 in rat hippocampal cultures augments expression of functional GABA synapses. The Journal of physiology 113 15961425
2015 KCC2 activity is critical in limiting the onset and severity of status epilepticus. Proceedings of the National Academy of Sciences of the United States of America 108 25733865
2002 Induction of NMDA and GABAA receptor-mediated Ca2+ oscillations with KCC2 mRNA downregulation in injured facial motoneurons. Journal of neurophysiology 104 12612004
2014 Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing. Cell research 99 24699064
2011 The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines. Proceedings of the National Academy of Sciences of the United States of America 97 21878564
2000 Localization and developmental expression patterns of the neuronal K-Cl cotransporter (KCC2) in the rat retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 97 10662832
2010 Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia. Archives of general psychiatry 92 20819979
2008 Sexually dimorphic expression of KCC2 and GABA function. Epilepsy research 90 18524541
2002 Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Brain research. Molecular brain research 90 12106695
2015 Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain. Cerebral cortex (New York, N.Y. : 1991) 88 26428952
2020 Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function. Frontiers in neurology 86 32010056
2017 GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl--sensitive WNK1 kinase. Nature communications 81 29176664
2017 APP modulates KCC2 expression and function in hippocampal GABAergic inhibition. eLife 80 28054918
2008 NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy research 79 18394864
2002 Developmental changes in KCC1, KCC2 and NKCC1 mRNAs in the rat cerebellum. Brain research. Developmental brain research 79 12101026
2016 Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay. Scientific reports 75 27436767
2012 Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 22496567
2021 The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2. Communications biology 71 33597714
2009 Novel repression of Kcc2 transcription by REST-RE-1 controls developmental switch in neuronal chloride. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 19923298
2017 KCC2, epileptiform synchronization, and epileptic disorders. Progress in neurobiology 65 29197650
2015 Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures. Neurobiology of disease 65 25562657
2017 KCC2 downregulation facilitates epileptic seizures. Scientific reports 55 28279020
2016 The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 55 27130838
2015 KCC2 Gates Activity-Driven AMPA Receptor Traffic through Cofilin Phosphorylation. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 26631461
2010 Premature expression of KCC2 in embryonic mice perturbs neural development by an ion transport-independent mechanism. The European journal of neuroscience 54 20529123
2014 Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain. JAMA neurology 52 24615367
2005 Brain-type creatine kinase activates neuron-specific K+-Cl- co-transporter KCC2. Journal of neurochemistry 51 16336223
2019 KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels. Cell reports 49 31269453
2016 Reduced Efficacy of the KCC2 Cotransporter Promotes Epileptic Oscillations in a Subiculum Network Model. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 27852771
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