Affinage

SLC12A5

Solute carrier family 12 member 5 · UniProt Q9H2X9

Length
1139 aa
Mass
126.2 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC12A5 (KCC2) is a CNS-specific K+-Cl- cotransporter that establishes the low intracellular Cl- required for hyperpolarizing GABAA receptor-mediated inhibition, expressed in neuronal somata and dendrites and co-localized with postsynaptic GABAA receptors (PMID:10212246, PMID:12106695). It mediates Cl--dependent K+ uptake whose activity is steeply regulated by phosphorylation, assembles into developmentally increasing SDS-resistant oligomers that parallel its functional activation, and its structural basis for ion transport and phospho-regulation is resolved by cryo-EM (PMID:12106695, PMID:17035525, PMID:33597714). KCC2 activity and surface stability are bidirectionally controlled by a phospho-code: PP1-mediated dephosphorylation of Ser940 downstream of NMDA receptor/Ca2+ signaling drives internalization and loss of inhibition, while WNK1-SPAK phosphorylation of Thr906/Thr1007 destabilizes surface KCC2; these sites set the timing of the developmental EGABA shift and gate activity-dependent and pathological downregulation (PMID:21532577, PMID:25733865, PMID:29176664, PMID:29092909, PMID:31396048). Surface levels are further tuned by trafficking and degradation machinery and by a broad interactome — gephyrin clustering, TGF-β2/CREB/Rab11b-driven membrane insertion, SNAP23/Syntaxin1A-dependent insertion, APP-mediated protection from ubiquitination, and E3 ligases Cbl-b and Fbxl4 that target KCC2 for proteasomal degradation (PMID:27505893, PMID:28054918, PMID:34810232, PMID:34048740, PMID:35118363, PMID:36973513). Independent of ion transport, KCC2 acts structurally through 4.1N- and Rac1/cofilin-dependent cytoskeletal signaling to regulate dendritic spine actin dynamics, AMPA receptor delivery and LTP, and its loss in mature neurons directly triggers apoptosis (PMID:20529123, PMID:26631461, PMID:33539918). Recessive loss-of-function SLC12A5 mutations that impair surface expression, glycosylation, and Cl- extrusion cause the human epilepsy syndrome EIMFS, and small-molecule KCC2 activators reverse Cl- accumulation in models of status epilepticus and spinal cord injury (PMID:26333769, PMID:27436767, PMID:30033363, PMID:36889319).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 Medium

    Established that KCC2 is a CNS-restricted plasma-membrane glycoprotein positioned at postsynaptic sites, defining it as a candidate for neuronal Cl- extrusion supporting GABAergic inhibition.

    Evidence Antibody-based immunolocalization in rat cerebellum with co-localization to GABAA receptor subunits

    PMID:10212246

    Open questions at the time
    • Did not demonstrate transport activity directly
    • No mechanism for how localization is maintained
  2. 2002 High

    Demonstrated that human KCC2 is a functional Cl--dependent K+ cotransporter whose activity is phosphorylation-dependent, providing the first kinetic and regulatory framework.

    Evidence Heterologous expression in Xenopus oocytes with 86Rb+ flux, kinetic analysis, and calyculin-A inhibition

    PMID:12106695

    Open questions at the time
    • Did not identify the responsible kinases or phospho-sites
    • Oocyte system lacks neuronal regulatory context
  3. 2006 High

    Showed KCC2 forms higher-order oligomers whose abundance rises developmentally in step with functional activation, linking quaternary structure to transporter competence.

    Evidence Native/reducing immunoblot, co-IP of tagged KCC2 in HEK293, microscopy and LSO electrophysiology

    PMID:17035525

    Open questions at the time
    • Causal role of oligomerization in transport not isolated from other developmental changes
    • Structural basis of oligomer interface not defined
  4. 2008 Medium

    Identified PAM as a C-terminal interactor that potentiates transport, an early example of partner-mediated activity regulation.

    Evidence Yeast two-hybrid, GST pull-down, co-IP and 86Rb+ flux with binding-deficient mutant in HEK293

    PMID:18769030

    Open questions at the time
    • Physiological relevance in neurons not established
    • Not connected to the later WNK-SPAK phospho-network
  5. 2010 High

    Revealed an ion-transport-independent structural function for KCC2 via 4.1N binding, distinguishing scaffolding roles from cotransport.

    Evidence Transgenic embryonic overexpression of transport-dead and 4.1N-binding-mutant KCC2 in mouse

    PMID:20529123

    Open questions at the time
    • Embryonic overexpression context differs from physiological neuronal expression
    • Downstream cytoskeletal effectors not fully mapped here
  6. 2011 High

    Defined a signaling-coupled erase mechanism: NMDA/Ca2+ activates PP1 to dephosphorylate Ser940, internalizing KCC2 and weakening inhibition.

    Evidence NMDA activation, phospho-Ser940 antibodies, surface biotinylation and perforated-patch EGABA in rat neurons

    PMID:21532577

    Open questions at the time
    • Kinase writing Ser940 not identified in this study
    • Reversibility/recovery mechanism beyond 20 min unresolved
  7. 2015 High

    Two complementary studies established the in vivo and clinical importance of KCC2: Ser940 phosphorylation protects activity during seizures, and recessive loss-of-function mutations cause human EIMFS epilepsy.

    Evidence S940A knockin mice in kainate SE model; whole-exome sequencing plus surface/glycosylation/Cl- assays of patient mutants

    PMID:25733865 PMID:26333769

    Open questions at the time
    • Genotype–phenotype correlation across mutation types incomplete
    • Whether all patient mutations act purely through surface loss unresolved
  8. 2015 High

    Demonstrated a transport-independent role for KCC2 in synaptic plasticity, coupling it to AMPA receptor trafficking and LTP through Rac1/cofilin/actin signaling.

    Evidence shRNA knockdown in hippocampal neurons with LTP, AMPAR trafficking, cofilin phosphorylation and transport-dead rescue

    PMID:26631461

    Open questions at the time
    • Direct molecular link between KCC2 and Rac1/PAK not structurally defined
    • Relationship to 4.1N pathway not reconciled
  9. 2016 High

    Characterized patient mutants electrophysiologically and identified TGF-β2/CREB/Rab11b as an upstream trafficking pathway, refining loss-of-function and surface-delivery mechanisms.

    Evidence Perforated-patch Cl- measurements of EIMFS mutants; primary neuron biochemistry, STED imaging and loss-of-function for TGF-β2 pathway

    PMID:27436767 PMID:27505893

    Open questions at the time
    • How Rab11b-dependent recycling integrates with phospho-regulation unclear
    • In vivo relevance of TGF-β2 pathway not tested
  10. 2017 High

    Expanded the interactome controlling KCC2 surface stability and function—APP protection, GABAA-driven Cl-/WNK1 confinement, and GABAB modulation—linking inhibitory tone directly to transporter trafficking.

    Evidence Co-IP, App knockout, single-particle tracking, phospho-Thr906/Thr1007 analysis and perforated-patch EGABA in hippocampal neurons

    PMID:28054918 PMID:28450542 PMID:29176664

    Open questions at the time
    • Hierarchy among competing surface regulators not established
    • Whether these pathways converge on the same KCC2 pool unknown
  11. 2017 High

    Pinpointed Thr1007 dephosphorylation as the dominant driver of pharmacological KCC2 activation, prioritizing the WNK-SPAK axis as a therapeutic target.

    Evidence NEM treatment with surface biotinylation, phospho-immunoblot, T1007A mutagenesis and electrophysiology in neurons

    PMID:29092909

    Open questions at the time
    • Selectivity of NEM beyond WNK-SPAK not fully excluded
    • Quantitative interplay with Ser940 not resolved
  12. 2018 High

    Demonstrated cell-type-specific therapeutic relevance by showing KCC2 in spinal inhibitory interneurons gates locomotor recovery after spinal cord injury.

    Evidence Small-molecule KCC2 agonist plus AAV KCC2 expression and DREADD hyperpolarization in inhibitory interneurons in a mouse SCI model

    PMID:30033363

    Open questions at the time
    • Molecular identity/binding site of the agonist not defined here
    • Circuit mechanism beyond interneuron hyperpolarization incomplete
  13. 2019 High

    Established that the KCC2 phospho-code sets developmental inhibition timing and adult behavior, with Ser940 and Thr906/Thr1007 acting bidirectionally.

    Evidence S940A and T906A/T1007A knockin mice with developmental EGABA recording and behavioral testing

    PMID:31396048

    Open questions at the time
    • Upstream developmental signals controlling these sites not identified
    • Mechanistic link from EGABA timing to cognitive/social deficits unresolved
  14. 2019 Medium

    Uncovered a transport-independent role in stabilizing Task-3 leak channels, extending KCC2's control of excitability beyond Cl- handling.

    Evidence Co-IP, surface expression and electrophysiology with KCC2 shRNA in rat dentate gyrus

    PMID:31269453

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Structural basis of KCC2–Task-3 interaction unknown
  15. 2021 High

    Provided structural and functional anchoring: cryo-EM defined transport-essential residues, conditional ablation showed KCC2 loss in mature neurons triggers apoptosis, and gephyrin was identified as a clustering scaffold.

    Evidence Cryo-EM of mouse KCC2; conditional KO with caspase/TTX dissection; proteomics and reciprocal co-IP for gephyrin with Cl- extrusion readout

    PMID:33539918 PMID:33597714 PMID:34810232

    Open questions at the time
    • Structural basis of phospho-regulation inferred, not directly captured with modified sites
    • Apoptotic signaling pathway from KCC2 loss not fully traced
  16. 2021 Medium

    Identified BDNF/TrkB/Cbl-b-mediated ubiquitination as a degradation route relevant to neuropathic pain, adding an E3 ligase to the KCC2 turnover machinery.

    Evidence Co-IP, ubiquitination assays, Cbl-b siRNA, TrkB inhibition and spared nerve injury behavioral testing

    PMID:34048740

    Open questions at the time
    • Single lab; ubiquitination site on KCC2 not mapped
    • Relationship to phospho-dependent degradation unclear
  17. 2022 Medium

    Defined SNAP23/Syntaxin1A-dependent membrane insertion downstream of mZnR/GPR39 and revealed NMDA-driven local transport reversal generating high-Cl- dendritic microdomains, broadening regulatory and functional context.

    Evidence Co-IP, truncation/phospho-mutants and IKK inhibition in HEK293/neurons; MQAE-FLIM Cl- imaging with SK-channel pharmacology

    PMID:35118363 PMID:36288701

    Open questions at the time
    • Single-lab findings
    • Physiological prevalence of transport reversal in vivo not established
  18. 2023 High

    Linked Fbxl4-mediated, Thr1007-dependent proteasomal degradation of KCC2 to anesthesia emergence and showed direct-binding small-molecule activators as anti-seizure therapeutics.

    Evidence Multiple anesthetic models with Fbxl4 identification, phospho-Thr1007 mutants and VPM electrophysiology; direct-binding compounds in benzodiazepine-resistant SE model

    PMID:36889319 PMID:36973513

    Open questions at the time
    • Binding site of activator compounds on KCC2 not structurally defined
    • How Fbxl4 selectivity for phospho-Thr1007 KCC2 is achieved unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the many surface-control inputs (phospho-code, oligomerization, gephyrin clustering, recycling, and competing E3 ligases) are integrated at a structural level to set KCC2 activity in a given neuron, and how transport-dependent versus transport-independent functions are partitioned.
  • No unified structural model coupling phosphorylation to the transport cycle with bound regulators
  • Hierarchy and crosstalk among Cbl-b, Fbxl4, and protective APP not defined
  • Molecular separation of scaffolding vs cotransport functions incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5357801 Programmed Cell Death 1
Partners
APPCBLBFBXL4GPHNKCNK9RAB11BSNAP23STX1A

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KCC2 is a ~140 kDa glycoprotein expressed exclusively in the CNS (not in axons or glia) and localizes to neuronal somata and dendrites at the plasma membrane, co-localizing with GABAA receptor β2/β3 subunits at cerebellar granule cell synapses, consistent with a postsynaptic Cl- extrusion role. Polyclonal antibody development against KCC2 fusion protein; immunolocalization in rat cerebellum; co-localization with GABAA receptor subunits by immunofluorescence The Journal of biological chemistry Medium 10212246
2002 Human KCC2 expressed in Xenopus oocytes mediates Cl--dependent 86Rb+ (K+) uptake under isotonic conditions and is activated ~20-fold by cell swelling under hypotonic conditions; this activation is blocked by the protein phosphatase inhibitor calyculin-A, indicating phosphorylation-dependent regulation. Km for K+ is 9.3 mM and for Cl- is 6.8 mM under isotonic conditions. Heterologous expression of hKCC2 cRNA in Xenopus oocytes; 86Rb+ flux assay; pharmacological inhibition with calyculin-A; kinetic analysis Brain research. Molecular brain research High 12106695
2004 KCC2 expression parallels neuronal maturation and the developmental decline in EGABA in spinal cord motoneurons and hippocampal pyramidal cells; phosphorylated KCC2 protein is present early in development before the functional GABA switch, suggesting tyrosine-phosphorylation is less important than transcriptional upregulation for developmental KCC2 activation. In situ hybridization; Western blot with phospho-specific analysis; developmental time-course in mouse embryonic and postnatal tissue The Journal of comparative neurology Medium 14648690
2006 KCC2 forms higher-order oligomers (dimers, trimers, tetramers of ~270, ~400, ~500 kDa) in mature brain; these oligomers are sulfhydryl-sensitive and SDS-resistant. The oligomer/monomer ratio increases developmentally (E18 to P30) in parallel with KCC2 functional activation. KCC2 homomers form when HA-tagged and His-tagged KCC2 are co-expressed in HEK-293 cells. Immunoblot analysis of native and reducing conditions; co-expression of epitope-tagged KCC2 in HEK-293 cells with co-immunoprecipitation; confocal and electron microscopy; electrophysiology in LSO neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 17035525
2008 The RCC1 domain of Protein Associated with Myc (PAM) binds to the carboxyl terminus of KCC2 (within a 20 amino acid region), and this interaction increases KCC2-mediated 86Rb+/K+ flux. A point mutation in the KCC2 C-terminus that abolishes PAM binding also abolishes N-ethylmaleimide (NEM)-induced activation of KCC2. Yeast two-hybrid; GST pull-down; co-immunoprecipitation in HEK293 cells; 86Rb+ uptake assay; site-directed mutagenesis Cellular physiology and biochemistry Medium 18769030
2010 Premature overexpression of KCC2 (including a transport-inactive N-terminal-deleted variant) in mouse embryos impairs neural tube and neural crest development through a Cl--transport-independent mechanism involving interaction with the cytoskeleton-associated protein 4.1N; a KCC2 mutant unable to bind 4.1N does not produce the embryonic phenotype. Neural-specific transgenic KCC2 overexpression in mouse embryos; transport-inactive KCC2 variant; 4.1N-binding mutant; analysis of neural tube thickness, neural crest cell patterning, cytoplasmic distribution of 4.1N and actin 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 function lasting >20 min, and a deficit in hyperpolarizing GABAergic inhibition. Blocking dephosphorylation of Ser940 reduces glutamate-induced KCC2 downregulation. Dissociated rat neurons; pharmacological NMDA receptor activation; phospho-specific antibodies for Ser940; surface biotinylation; gramicidin-perforated patch-clamp for EGABA; PP1 inhibitors Nature neuroscience High 21532577
2013 WNK1 kinase regulates KCC2 transcript levels; loss of WNK1/HSN2 isoform in zebrafish increases kcc2 mRNA expression, and overexpression of human KCC2 (including a transport-inactive C568A mutant) phenocopies the wnk1/hsn2 knockdown lateral line development defect; double knockdown of wnk1/hsn2 and kcc2 rescues the phenotype, establishing a genetic pathway. Morpholino knockdown in zebrafish; KCC2 mRNA overexpression; transport-inactive KCC2-C568A mutant; double knockdown epistasis; in situ hybridization; semi-quantitative RT-PCR PLoS genetics High 23300475
2015 Phosphorylation of KCC2 at Ser940 is critical for potentiating KCC2 activity during status epilepticus (SE): kainate-induced SE causes dephosphorylation of S940 and KCC2 internalization in wild-type mice, whereas S940A knockin mice (which cannot be phosphorylated at S940) exhibit rapid lethality upon kainate injection and selective KCC2 activity deficit after transient glutamate exposure that cannot be rescued by agents that normally enhance S940 phosphorylation. S940A knockin mice; kainate SE model; surface biotinylation; phospho-specific immunoblot; gramicidin-perforated patch-clamp in cultured hippocampal neurons; pharmacological manipulation of S940 phosphorylation Proceedings of the National Academy of Sciences of the United States of America High 25733865
2015 Recessive loss-of-function SLC12A5 mutations in EIMFS patients cause decreased KCC2 surface expression, reduced protein glycosylation, and impaired Cl- extrusion, establishing that KCC2 dysfunction directly causes a human epilepsy syndrome. Whole exome sequencing; surface expression assay; glycosylation analysis; gramicidin-perforated patch-clamp for intracellular Cl-; heterologous expression of mutant KCC2 Nature communications High 26333769
2015 Suppressing KCC2 expression in rat hippocampal neurons prevents activity-driven AMPA receptor membrane delivery and blocks LTP, through a mechanism independent of KCC2 transporter function; this is mediated by increased Rac1/PAK-LIMK-dependent cofilin phosphorylation and actin polymerization in dendritic spines. shRNA knockdown of KCC2 in hippocampal neurons; LTP induction; AMPA receptor surface trafficking assay; cofilin phosphorylation measurement; rescue with transport-inactive KCC2 The Journal of neuroscience : the official journal of the Society for Neuroscience High 26631461
2016 Gramicidin-perforated patch-clamp of EIMFS patient-derived KCC2 mutants (E50_Q93del, M415V, A191V, S323P) in heterologous expression demonstrates variable degrees of suppressed Cl- extrusion; compound heterozygous expression of two mutants produces intracellular Cl- intermediate between WT and no-KCC2, confirming partial loss-of-function mechanism. Gramicidin-perforated patch-clamp; heterologous expression of mutant KCC2; measurement of intracellular Cl- concentration; whole exome sequencing Scientific reports High 27436767
2016 TGF-β2 promotes KCC2 membrane trafficking and functional activation via a signaling pathway through CREB phosphorylation and upregulation of Rab11b; TGF-β2 increases KCC2-Rab11b co-localization and interaction, and loss of CREB1 or Rab11b suppresses TGF-β2-dependent KCC2 surface expression and Cl- extrusion. Primary hippocampal neurons; immunoblotting; surface biotinylation; immunofluorescence; 3D-STED microscopy; co-immunoprecipitation; KCC2-mediated Cl- extrusion assay; CREB and Rab11b loss-of-function Journal of cell science High 27505893
2017 APP physically interacts with KCC2 at the synapse; APP deficiency reduces total and membrane KCC2 levels, causing a depolarizing shift in EGABA, reduced GABAAR α1 subunit levels, and impaired unitary IPSC amplitudes. APP functions to limit tyrosine-phosphorylation and ubiquitination of KCC2, preventing its degradation. Co-immunoprecipitation; biochemical fractionation; electrophysiology (simultaneous presynaptic AP and IPSC recording); App knockout mice; KCC2 rescue experiments; ubiquitination and tyrosine-phosphorylation assays eLife High 28054918
2017 GABAA receptor-mediated inhibition confines KCC2 to the plasma membrane via a Cl--dependent mechanism requiring WNK1 kinase phosphorylation of KCC2 at Thr906 and Thr1007; blocking inhibition increases KCC2 lateral diffusion and endocytosis, while enhancing inhibition stabilizes surface KCC2. Mature hippocampal neurons; surface biotinylation; single-particle tracking (lateral diffusion); pharmacological manipulation of GABAA receptors; phospho-specific antibodies; WNK1 pathway analysis; KCC2 endocytosis assay Nature communications High 29176664
2017 GABAB receptors physically associate with KCC2; activation of GABAB receptors reduces KCC2 surface expression and function, shifting EGABA, providing a mechanism by which metabotropic GABA signaling modulates ionotropic GABAergic inhibition. Co-immunoprecipitation from rodent hippocampus; surface biotinylation; gramicidin-perforated patch-clamp for EGABA; pharmacological GABABR activation in hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 28450542
2017 N-ethylmaleimide (NEM) increases KCC2 activity by increasing Ser940 phosphorylation, decreasing Thr1007 phosphorylation (via inhibition of WNK-SPAK signaling), and increasing KCC2 surface levels; mutational analysis reveals that Thr1007 dephosphorylation is the primary mediator of NEM-induced KCC2 activation. Surface biotinylation; phospho-specific immunoblot; electrophysiology; site-directed mutagenesis (T1007A); WNK-SPAK pathway analysis in neurons The Journal of biological chemistry High 29092909
2018 A small-molecule KCC2 agonist restores stepping ability in mice with spinal cord injury; selective expression of KCC2 or hyperpolarizing DREADDs in inhibitory interneurons mimics this recovery, demonstrating that KCC2 in spinal inhibitory interneurons is the functional locus mediating relay circuit activation. Small-molecule screen; bilateral hemisection mouse SCI model; AAV-mediated selective KCC2 expression in inhibitory interneurons; DREADD hyperpolarization; behavioral stepping assay Cell High 30033363
2019 KCC2 interacts with Task-3 (KCNK9) leak potassium channels and is required for their membrane expression; KCC2 knockdown reduces Task-3 surface expression, depolarizes resting membrane potential, and increases neuronal excitability independently of changes in EGABA. Co-immunoprecipitation; surface expression assay; electrophysiology (resting potential, input resistance); KCC2 knockdown by shRNA in rat dentate gyrus; in vivo recordings Cell reports Medium 31269453
2019 Developmental regulation of KCC2 phosphorylation at Ser940 and at Thr906/Thr1007 controls the timing of the postnatal EGABA shift: S940A knockin mice delay onset of hyperpolarizing inhibition, while T906A/T1007A knockin mice accelerate it; both mutations produce long-term cognitive and social behavior deficits in adult mice. S940A and T906A/T1007A knockin mice; gramicidin-perforated patch-clamp for developmental EGABA; behavioral testing (social behavior, memory retention) Frontiers in molecular neuroscience High 31396048
2021 Cryo-EM structures of mouse KCC2 and human NKCC1 reveal essential residues for ion transport and provide structural basis for understanding how phosphorylation regulates cotransporter activity. Cryo-electron microscopy; computational analysis; functional characterization of structure-guided mutants Communications biology High 33597714
2021 Conditional ablation of KCC2 in mature neurons rapidly activates the extrinsic apoptotic pathway; direct pharmacological inhibition of KCC2 in mature neurons is sufficient to induce apoptosis even when neuronal depolarization is blocked by TTX. In contrast, ablating KCC2 in immature neurons does not affect neuronal development or dendritic architecture but prevents postnatal development of hyperpolarizing GABAAR currents. Conditional KCC2 knockout in developing vs. mature neurons; caspase activation assay; TTX blockade; dendritic morphology analysis; gramicidin-perforated patch-clamp The Journal of biological chemistry High 33539918
2021 Gephyrin (the main scaffolding protein at GABAergic synapses) interacts with endogenous KCC2; gephyrin stabilizes plasmalemmal KCC2 and promotes its clustering near GABAergic synapses in hippocampal neurons, thereby controlling KCC2-mediated Cl- extrusion. Proteomics (mass spectrometry) of KCC2 interactors in adult rat neocortex; co-immunoprecipitation from neocortical extracts; surface expression assay; Cl- extrusion measurement; fluorescence imaging of KCC2 clustering The Journal of neuroscience : the official journal of the Society for Neuroscience High 34810232
2021 BDNF treatment promotes KCC2 ubiquitination in spinal cord dorsal horn via the E3 ubiquitin ligase Cbl-b, leading to KCC2 degradation; KCC2 interacts with Cbl-b, and Cbl-b knockdown reduces KCC2 ubiquitination and attenuates BDNF-induced pain hypersensitivity; spared nerve injury increases KCC2 ubiquitination through TrkB receptor activation. Co-immunoprecipitation; ubiquitination assay; Cbl-b siRNA knockdown; TrkB inhibition; spared nerve injury model; behavioral pain testing European journal of pharmacology Medium 34048740
2022 KCC2 interacts with SNARE protein SNAP23; the KCC2 C-terminal domain is required for membrane targeting and SNAP23-dependent upregulation of KCC2 activity triggered by mZnR/GPR39 activation. SNAP23, Syntaxin 1A, and KCC2 all show increased membrane insertion following mZnR/GPR39 activation; inhibiting IKK (SNAP23's upstream activator) prevents this upregulation. Co-immunoprecipitation; KCC2 truncation mutants; SNAP23 phosphorylation-insensitive mutants; IKK inhibition; KCC2 activity assay in HEK293 cells and mouse hippocampal neurons; surface expression measurement iScience Medium 35118363
2022 NMDA receptor activation drives KCC2 to reverse its transport direction at sites of dendritic blebbing: Ca2+ influx activates SK channels, causing sustained local K+ efflux that increases extracellular [K+] sufficiently to reverse KCC2-mediated K+-Cl- cotransport, generating high-[Cl-] microdomains at dendritic blebs. Whole-cell patch clamp; MQAE-FLIM chloride imaging in dendrites; pharmacological dissection (NMDA, SK channel blockers); spatiotemporal mapping of dendritic [Cl-] Cell reports Medium 36288701
2023 KCC2 downregulation in the ventral posteromedial thalamus (VPM) is a common mechanism for emergence of consciousness from anesthesia: diverse anesthetics trigger ubiquitin-proteasomal degradation of KCC2 via E3 ligase Fbxl4, which is promoted by KCC2 phosphorylation at Thr1007; this KCC2 loss causes GABAA receptor-mediated disinhibition and accelerated recovery of VPM neuron excitability. Mouse anesthesia models (multiple anesthetics); KCC2 knockout/knockdown in VPM; Fbxl4 identification; co-immunoprecipitation of KCC2-Fbxl4; phospho-Thr1007 mutants; proteasome inhibitors; electrophysiology of VPM neurons; behavioral emergence assays Nature neuroscience High 36973513
2023 Small molecules that directly bind to and activate KCC2 reduce neuronal Cl- accumulation and excitability, prevent development of and terminate benzodiazepine-resistant status epilepticus, and reduce neuronal cell death following SE. Small molecule screening; direct binding assay; neuronal Cl- measurement; electrophysiology; in vivo benzodiazepine-resistant SE model in mice; neuronal death quantification Cell reports. Medicine High 36889319

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. The Journal of physiology 322 15528236
2011 Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. The Journal of neuroscience : the official journal of the Society for Neuroscience 257 21795557
2011 NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nature neuroscience 246 21532577
2004 Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride. The Journal of comparative neurology 227 14648690
2012 Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology 213 22705273
2002 Reduction of KCC2 expression and GABAA receptor-mediated excitation after in vivo axonal injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 199 12040048
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 175 24139641
2014 GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 151 25066727
2018 Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations. Cell 150 30033363
2015 Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nature communications 130 26333769
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 109 25733865
2005 KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. The European journal of neuroscience 104 15932617
2014 Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing. Cell research 99 24699064
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 91 18524541
2015 Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain. Cerebral cortex (New York, N.Y. : 1991) 90 26428952
2002 Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Brain research. Molecular brain research 90 12106695
2020 Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function. Frontiers in neurology 89 32010056
2015 Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Frontiers in cellular neuroscience 85 26528127
2017 APP modulates KCC2 expression and function in hippocampal GABAergic inhibition. eLife 83 28054918
2017 GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl--sensitive WNK1 kinase. Nature communications 82 29176664
2016 Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay. Scientific reports 77 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 73 33597714
2017 KCC2, epileptiform synchronization, and epileptic disorders. Progress in neurobiology 66 29197650
2003 Sex-specific KCC2 expression and GABA(A) receptor function in rat substantia nigra. Experimental neurology 61 14552904
2015 KCC2 function modulates in vitro ictogenesis. Neurobiology of disease 58 25926348
2017 KCC2 downregulation facilitates epileptic seizures. Scientific reports 56 28279020
2016 The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 56 27130838
2010 Premature expression of KCC2 in embryonic mice perturbs neural development by an ion transport-independent mechanism. The European journal of neuroscience 55 20529123
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
2014 Therapeutic restoration of spinal inhibition via druggable enhancement of potassium-chloride cotransporter KCC2-mediated chloride extrusion in peripheral neuropathic pain. JAMA neurology 53 24615367
2015 Kinase-KCC2 coupling: Cl- rheostasis, disease susceptibility, therapeutic target. Journal of neurophysiology 52 26510764
2019 KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels. Cell reports 50 31269453
2019 Role of the BDNF-TrkB pathway in KCC2 regulation and rehabilitation following neuronal injury: A mini review. Neurochemistry international 49 30986502
2023 Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment. Acta pharmacologica Sinica 47 37704745
2021 Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury. Experimental neurology 46 33453210
2020 The Expanding Therapeutic Potential of Neuronal KCC2. Cells 45 31963584
2006 Regulation of KCC2 and NKCC during development: membrane insertion and differences between cell types. The Journal of comparative neurology 45 16958091
2017 Enhancing KCC2 function counteracts morphine-induced hyperalgesia. Scientific reports 44 28634406
2014 Down-regulation of KCC2 expression and phosphorylation in motoneurons, and increases the number of in primary afferent projections to motoneurons in mice with post-stroke spasticity. PloS one 43 25546454
2016 Diminished KCC2 confounds synapse specificity of LTP during senescence. Nature neuroscience 42 27500406
2020 Environmental regulation of the chloride transporter KCC2: switching inflammation off to switch the GABA on? Translational psychiatry 41 33060559
2017 Neuronal Chloride Regulation via KCC2 Is Modulated through a GABAB Receptor Protein Complex. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 28450542
2023 Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules (Basel, Switzerland) 39 36771011
2018 Pathogenic potential of human SLC12A5 variants causing KCC2 dysfunction. Brain research 39 30576625
2018 KCC2 Regulates Dendritic Spine Formation in a Brain-Region Specific and BDNF Dependent Manner. Cerebral cortex (New York, N.Y. : 1991) 38 30169756
2019 Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function. Frontiers in molecular neuroscience 37 31396048
2017 A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures. Clinical genetics 37 28477354
2014 Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons. Frontiers in cellular neuroscience 34 24478630
2019 Sevoflurane-Induced Dysregulation of Cation-Chloride Cotransporters NKCC1 and KCC2 in Neonatal Mouse Brain. Molecular neurobiology 32 31493242
2017 N-Ethylmaleimide increases KCC2 cotransporter activity by modulating transporter phosphorylation. The Journal of biological chemistry 32 29092909
2015 Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. Brain structure & function 32 26427846
2023 Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice. Cell reports. Medicine 31 36889319
2023 Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus. Nature neuroscience 31 36973513
2019 Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K+-Cl- Cotransporter KCC2. BioMed research international 31 31240228
2014 K-Cl cotransporter KCC2--a moonlighting protein in excitatory and inhibitory synapse development and function. Pflugers Archiv : European journal of physiology 31 24909111
2012 Rapamycin down-regulates KCC2 expression and increases seizure susceptibility to convulsants in immature rats. Neuroscience 31 22613737
2018 Dose-dependent reversal of KCC2 hypofunction and phenobarbital-resistant neonatal seizures by ANA12. Scientific reports 30 30097625
2014 BDNF modifies hippocampal KCC2 and NKCC1 expression in a temporal lobe epilepsy model. Acta neurobiologiae experimentalis 30 25231847
2022 KCC2 drives chloride microdomain formation in dendritic blebbing. Cell reports 25 36288701
2023 BDNF-TrkB signaling pathway-mediated microglial activation induces neuronal KCC2 downregulation contributing to dynamic allodynia following spared nerve injury. Molecular pain 24 37321969
2019 Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2. The journal of pain 24 31085334
2021 Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model. Science signaling 23 34752143
2020 SLC12A5 interacts and enhances SOX18 activity to promote bladder urothelial carcinoma progression via upregulating MMP7. Cancer science 22 32449280
2022 Acupuncture improves the structure of spastic muscle and decreases spasticity by enhancing GABA, KCC2, and GABAAγ2 in the brainstem in rats after ischemic stroke. Neuroreport 21 35594431
2019 KCC2 membrane diffusion tunes neuronal chloride homeostasis. Neuropharmacology 21 30871970
2016 The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-β2. Journal of cell science 21 27505893
2013 WNK1/HSN2 mutation in human peripheral neuropathy deregulates KCC2 expression and posterior lateral line development in zebrafish (Danio rerio). PLoS genetics 21 23300475
2022 The role of KCC2 and NKCC1 in spinal cord injury: From physiology to pathology. Frontiers in physiology 20 36589461
2019 Traumatic Brain Injury Temporal Proteome Guides KCC2-Targeted Therapy. Journal of neurotrauma 20 31122143
2023 SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes. Cancer medicine 19 36645171
2021 KCC2 is required for the survival of mature neurons but not for their development. The Journal of biological chemistry 19 33539918
2021 Gephyrin Interacts with the K-Cl Cotransporter KCC2 to Regulate Its Surface Expression and Function in Cortical Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 34810232
2018 M-Calpain Activation Facilitates Seizure Induced KCC2 Down Regulation. Frontiers in molecular neuroscience 19 30186110
2020 Staurosporine and NEM mainly impair WNK-SPAK/OSR1 mediated phosphorylation of KCC2 and NKCC1. PloS one 18 32413057
2018 KCC2-GABAA pathway correlates with the analgesic effect of electro-acupuncture in CCI rats. Molecular medicine reports 18 29568893
2015 The K(+)-Cl(-) Cotransporter KCC2 and Chloride Homeostasis: Potential Therapeutic Target in Acute Central Nervous System Injury. Molecular neurobiology 18 25941074
2022 Body Weight-Supported Treadmill Training Ameliorates Motoneuronal Hyperexcitability by Increasing GAD-65/67 and KCC2 Expression via TrkB Signaling in Rats with Incomplete Spinal Cord Injury. Neurochemical research 17 35320460
2022 Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion. Brain and behavior 16 35106976
2019 NR2B receptor- and calpain-mediated KCC2 cleavage resulted in cognitive deficiency exposure to isoflurane. Neurotoxicology 16 31672664
2008 The RCC1 domain of protein associated with Myc (PAM) interacts with and regulates KCC2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 18769030
2022 KCC2 receptor upregulation potentiates antinociceptive effect of GABAAR agonist on remifentanil-induced hyperalgesia. Molecular pain 15 35352582
2021 LIFU Alleviates Neuropathic Pain by Improving the KCC2 Expression and Inhibiting the CaMKIV-KCC2 Pathway in the L4-L5 Section of the Spinal Cord. Neural plasticity 15 33953740
2017 Neuroprotection by Propofol Post-Conditioning: Focus on PKMζ/KCC2 Pathway Activity. Cellular and molecular neurobiology 15 28779332
2015 Effects of SPAK knockout on sensorimotor gating, novelty exploration, and brain area-dependent expressions of NKCC1 and KCC2 in a mouse model of schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 15 25797415
2023 CRISPR-Based KCC2 Upregulation Attenuates Drug-Resistant Seizure in Mouse Models of Epilepsy. Annals of neurology 14 37014252
2022 Time-restricted feeding entrains long-term behavioral changes through the IGF2-KCC2 pathway. iScience 14 35521538
2021 BDNF modulated KCC2 ubiquitylation in spinal cord dorsal horn of mice. European journal of pharmacology 14 34048740
2020 The role of KCC2 in hyperexcitability of the neonatal brain. Neuroscience letters 14 32860887
2016 Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures. Neurobiology of disease 14 26875662
2014 The KCl-cotransporter KCC2 linked to epilepsy. EMBO reports 14 24928907
2022 Loss of KCC2 in GABAergic Neurons Causes Seizures and an Imbalance of Cortical Interneurons. Frontiers in molecular neuroscience 13 35370549
2015 Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain. Cell death & disease 13 26043076
2023 KCC2 downregulation after sciatic nerve injury enhances motor function recovery. Scientific reports 12 37188694
2022 SNAP23 regulates KCC2 membrane insertion and activity following mZnR/GPR39 activation in hippocampalneurons. iScience 12 35118363

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