Affinage

SLC12A6

Solute carrier family 12 member 6 · UniProt Q9UHW9

Length
1150 aa
Mass
127.6 kDa
Annotated
2026-06-10
49 papers in source corpus 26 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC12A6 encodes KCC3, an electroneutral K+-Cl- cotransporter that couples K+ and Cl- efflux to drive regulatory volume decrease and set intracellular chloride (PMID:10347194, PMID:32506846). The protein adopts a 12-transmembrane topology with a large TM5-TM6 extracellular loop and extensive cytoplasmic N- and C-termini, and is activated specifically by cell swelling, with greater volume sensitivity than KCC1 (PMID:10347194, PMID:10600773). KCC3 activity is governed by a multi-site phosphorylation switch: WNK3, acting with the SPAK/MO25 kinase module, phosphorylates Ser-96, Thr-991, and Thr-1048 to hold the transporter inactive under isotonic conditions, while swelling-triggered dephosphorylation at these sites activates transport; combined alanine substitution renders KCC3 constitutively active and refractory to hypotonicity (PMID:24043619, PMID:26217182). Surface abundance is independently tuned by tyrosine phosphorylation, including SYK-mediated phosphorylation of an N-terminal tyrosine that reduces plasma membrane levels (PMID:31145900). Alternative promoter usage and splicing generate multiple N-terminal isoforms with tissue-specific distribution — brain-predominant KCC3a and kidney proximal tubule basolateral KCC3b — all swelling-activated (PMID:11246162, PMID:16048901). KCC3 is essential for cell volume homeostasis in neurons and renal tubules: in peripheral nerve it controls axon volume during early postnatal development, and its loss causes axonal swelling preceding myelin degeneration (PMID:17659877, PMID:32506846). Both loss-of-function (e.g. the ACCPN-causing 2436delG truncation) and gain-of-function (constitutive T991A activity) disrupt this finely tuned volume control to cause peripheral neuropathy, the latter by excessively depleting intracellular K+ (PMID:12368912, PMID:26217182, PMID:27485015). Loss of KCC3 specifically in parvalbumin-positive neurons during a critical perinatal window produces the locomotor deficits of HMSN/ACC (ACCPN), and the disease is irreversible once established (PMID:25116249, PMID:33596149). KCC3 also contributes to renal ion handling and blood pressure, with knockout hypertension being neurogenic in origin via elevated sympathetic tone (PMID:16424367, PMID:35874803).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established the fundamental molecular identity of KCC3 as a swelling-activated K+-Cl- cotransporter, defining the biochemical activity that all later regulation and disease work builds on.

    Evidence Heterologous expression in Xenopus oocytes and HEK-293 cells with 86Rb+ flux assays and hydropathy analysis

    PMID:10347194 PMID:10600773

    Open questions at the time
    • No structure of the transporter resolved
    • Endogenous physiological substrate concentrations not addressed
  2. 2001 Medium

    Mapped KCC3 expression to specific CNS structures and resolved two tissue-specific isoforms, framing how a single gene serves distinct neuronal and renal roles.

    Evidence KCC3-specific antibody Western blot, Northern blot, and immunofluorescence of mouse brain

    PMID:11246162

    Open questions at the time
    • Functional difference between isoforms not yet tested
    • Single-lab antibody characterization
  3. 2002 High

    Linked KCC3 to human disease (ACCPN) and to nervous system development, showing a membrane-localized but transport-dead mutant and a knockout neuropathy phenotype — separating trafficking from function.

    Evidence Oocyte reconstitution of disease mutant plus targeted Slc12a6 deletion in mice with behavioral/electrophysiological phenotyping

    PMID:12368912

    Open questions at the time
    • Did not identify the cell type responsible for neuropathy
    • Did not define the molecular switch controlling activity
  4. 2003 High

    Demonstrated that KCC3 loss impairs cell volume regulation across renal tubules and neurons and produces multi-system pathology, establishing volume homeostasis as the core in vivo function.

    Evidence Independent KCC3 knockout mouse with cell volume measurements, electrocorticogram, blood pressure, and inner ear morphology

    PMID:14532115

    Open questions at the time
    • Origin of hypertension not yet determined
    • Cell-autonomous vs systemic contributions unresolved
  5. 2005 High

    Defined the full isoform repertoire, transport kinetics, and renal localization, refining the molecular and tissue-level picture of KCC3.

    Evidence Northern/Western blot, kidney immunofluorescence, and kinetic 86Rb+ flux in oocytes

    PMID:16048901

    Open questions at the time
    • Functional specialization of minor isoforms unclear
  6. 2006 High

    Resolved the origin of knockout hypertension as neurogenic rather than vascular-intrinsic, showing KCC3 acts on the nervous system to set sympathetic tone.

    Evidence VSMC Cl- measurement, ex vivo vascular reactivity, in vivo adrenergic/ganglionic blockade, urinary catecholamines in KCC3 KO mice

    PMID:16424367

    Open questions at the time
    • Specific neuronal circuit mediating sympathetic activation not identified
  7. 2007 High

    Pinpointed the temporal and cellular sequence of peripheral nerve pathology — axonal swelling preceding myelin loss — implicating volume dysregulation as the primary insult.

    Evidence Morphometry of sciatic nerve across postnatal timepoints, nerve conduction velocity, and IGF-1 pathway analysis in KCC3 KO mice and cell models

    PMID:17133354 PMID:17659877

    Open questions at the time
    • Did not establish which nerve cell type requires KCC3
    • Link between proliferative signaling and neuropathy unclear
  8. 2012 High

    Genetically dissected neuronal versus non-neuronal KCC3 contributions, attributing neuropathy to neuronal axon volume control and auditory deficits to non-neuronal cells, and confirmed Cl- extrusion in sensory neurons.

    Evidence Conditional Cre/loxP mice and gramicidin-perforated patch clamp in KCC3-/- DRG neurons

    PMID:22423107 PMID:22609694

    Open questions at the time
    • Did not yet pinpoint the exact neuronal subtype driving locomotor disease
  9. 2013 High

    Identified trafficking determinants and a dominant-negative mechanism via heterodimerization, showing how mislocalizing mutations impair both KCC3 and partner cotransporters.

    Evidence Co-immunoprecipitation with KCC2, glycosylation/confocal trafficking analysis, and oocyte function for the E289G mutant

    PMID:23593405

    Open questions at the time
    • Physiological relevance of KCC3-KCC2 heterodimers in vivo not shown
    • Single-lab data
  10. 2013 High

    Defined the phosphoregulatory switch by identifying SPAK/MO25- and WNK3-dependent phosphosites that tonically inhibit the transporter, explaining how activity is coupled to cell volume.

    Evidence In vitro kinase assays, site-directed mutagenesis of Ser-96/Thr-991/Thr-1048, and oocyte/HEK293 functional validation

    PMID:24043619

    Open questions at the time
    • Identity of the activating phosphatase not established
    • In vivo phosphosite occupancy not measured
  11. 2014 High

    Established Thr-991/Thr-1048 as a potent activity switch capable of 25-fold activation and depletion of intracellular K+, and identified the parvalbumin-positive neuron as the critical cell type for ACCPN.

    Evidence Mutagenesis with K+/transport assays and pharmacological dissection; four cell-type-specific Cre/loxP knockout lines with locomotor testing; KCC3-driven NF-κB/SPAK tumor signaling

    PMID:24655550 PMID:25116249 PMID:26217182

    Open questions at the time
    • Mechanism linking PV neuron volume defect to motor circuitry dysfunction unresolved
  12. 2016 High

    Demonstrated that gain-of-function over-activation of KCC3 is itself pathogenic, establishing that both excess and absence of transport cause neurodegeneration via volume imbalance.

    Evidence Exome sequencing of a patient, patient-cell volume assay, and T991A/T1048A knock-in mice with electrophysiology and histopathology

    PMID:27485015

    Open questions at the time
    • Why constitutive K+ loss is selectively neurotoxic not fully mechanistic
  13. 2019 Medium

    Showed that tyrosine phosphorylation by SYK controls KCC3 surface abundance, adding a membrane-trafficking layer distinct from the WNK/SPAK serine/threonine switch.

    Evidence SYK depletion/inhibition and constitutively active SYK overexpression with plasma membrane abundance quantification in HEK cells

    PMID:31145900

    Open questions at the time
    • The specific tyrosine residue not definitively mapped in narrative detail
    • In vivo relevance untested
  14. 2020 High

    Directly visualized that KCC3 LOF abolishes regulatory volume decrease while GOF blunts swelling in sensory neurons, cementing the bidirectional role of KCC3 in neuronal volume homeostasis.

    Evidence Calcein wide-field cell volume imaging in DRG neurons from WT, LOF, and GOF mouse lines

    PMID:32506846

    Open questions at the time
    • Did not connect single-cell volume defect to whole-organism phenotype timing
  15. 2021 Medium

    Defined the developmental window of KCC3 requirement, showing function is needed perinatally and that disease is irreversible, with implications for therapeutic timing.

    Evidence Tamoxifen-inducible PV-CreERT2 deletion/re-expression in adult mice with rotarod and gait testing; ZnR/GPR39-driven KCC3 recruitment to protrusions in cancer cells

    PMID:33465674 PMID:33596149

    Open questions at the time
    • Molecular basis of the irreversibility not defined
    • Adult re-expression rescue mechanism unexplored
  16. 2023 Medium

    Characterized renal KCC3a regulation, localizing it to specific intercalated cells and showing posttranscriptional upregulation by bicarbonate and volume status independent of pendrin and aldosterone.

    Evidence Isoform-specific antibody immunofluorescence, dietary loading, and immunoblotting in WT and pendrin KO mice

    PMID:35874803 PMID:37036298

    Open questions at the time
    • Posttranscriptional mechanism stabilizing KCC3a protein unidentified
    • Functional role in acid-base handling not directly tested
  17. 2025 Medium

    Extended KCC3's renal role to basal NCC regulation in the distal convoluted tubule and identified an additional mislocalizing disease mutation linking KCC3 dysfunction to cellular senescence.

    Evidence DCT-specific conditional KO with NCC immunoblotting/RT-qPCR; patient-cell localization, ion measurement, and senescence marker analysis for p.H371R

    PMID:39988558 PMID:40875335

    Open questions at the time
    • Mechanism by which KCC3 controls NCC expression unknown
    • Causal link between mislocalization and senescence not mechanistically established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how perinatal KCC3-dependent volume control becomes permanently fixed into irreversible axonal pathology, and what phosphatase/upstream signals reverse the WNK/SPAK inhibitory phosphorylation during swelling.
  • Activating phosphatase for Ser-96/Thr-991/Thr-1048 not identified
  • Molecular basis of developmental irreversibility unknown
  • No high-resolution structure of human KCC3

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-382551 Transport of small molecules 3
Partners
KCC2MO25SPAKSYKWNK3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KCC3 functions as a K+-Cl- cotransporter: expression in Xenopus laevis oocytes demonstrated Cl--dependent uptake of 86Rb+ that is strongly activated by cell swelling and weakly sensitive to furosemide. KCC3 has greater volume sensitivity than KCC1. Heterologous expression in Xenopus laevis oocytes, 86Rb+ flux assay The Journal of biological chemistry High 10347194
1999 KCC3 protein has 12 predicted transmembrane domains, a large extracellular loop between TM5 and TM6, and large NH2- and COOH-terminal cytoplasmic domains. It is activated by cell swelling, N-ethylmaleimide treatment, and staurosporine when transiently expressed in HEK-293 cells. Hydropathy analysis, transient transfection in HEK-293 cells, ion transport assay The American journal of physiology High 10600773
2002 A truncating frameshift mutation in KCC3 (2436delG, Thr813fsX813) causing ACCPN produces a protein that is correctly glycosylated and expressed at the plasma membrane but is non-functional as a K+-Cl- cotransporter. Heterologous expression of wild-type and mutant KCC3 in Xenopus laevis oocytes, ion flux assay, glycosylation analysis Nature genetics High 12368912
2002 Mice with targeted deletion of Slc12a6 (KCC3 knockout) develop locomotor deficit, peripheral neuropathy, and sensorimotor gating deficit, demonstrating a critical role for KCC3 in development and maintenance of the nervous system. Targeted gene deletion in mice, behavioral and electrophysiological phenotyping Nature genetics High 12368912
2003 KCC3 knockout mice show severely impaired cell volume regulation in renal tubules and neurons, moderately raised intraneuronal Cl- concentration, progressive neurodegeneration of peripheral and central nervous system, reduced seizure threshold, arterial hypertension, and slowly progressive deafness with degeneration of inner ear K+ recycling pathway cells. Targeted gene disruption in mice, cell volume measurements, electrocorticogram, blood pressure measurement, morphological analysis of inner ear The EMBO journal High 14532115
2001 KCC3 is localized to myelin sheaths in spinal cord white matter tracts, pyramidal neurons, Purkinje cells, and the base of choroid plexus epithelium in mouse CNS. Two distinct protein isoforms (150 kDa in kidney, 170 kDa in brain) exist even after deglycosylation, corresponding to KCC3a (brain-predominant) and KCC3b (kidney-predominant) isoforms generated by alternative first coding exons. Western blot with KCC3-specific polyclonal antibody, Northern blot, immunofluorescence microscopy of mouse brain sections Neuroscience Medium 11246162
2001 KCC3 expression and activity are regulated by tyrosine phosphorylation, and KCC3 promotes cell proliferation and cell cycle progression; IGF-1 upregulates KCC3 expression and stimulates growth, while TNF-alpha downregulates KCC3 and causes growth arrest. NIH/3T3 fibroblast expression system, DIOA inhibition, FACS cell cycle analysis, Western blot for Rb and cdc2 phosphorylation Proceedings of the National Academy of Sciences of the United States of America Medium 11724933
2005 KCC3 has at least five NH2-terminal isoforms (KCC3a, KCC3b, KCC3a-x2M, KCC3b-x2M, KCC3a-S) generated by alternative promoter usage and splicing. All are activated by cell swelling but not under isotonic conditions. KCC3a kinetics: Km for Rb+ ~10.7 mM, Cl- ~7.3 mM; anion selectivity Br- > Cl- > PO4 = I- = SCN- = gluconate. KCC3b predominates in kidney proximal tubule at basolateral membrane. Northern blot, Western blot, immunofluorescence of mouse/rat kidney, functional expression in Xenopus laevis oocytes with 86Rb+ flux assay American journal of physiology. Renal physiology High 16048901
2006 Hypertension in KCC3 knockout mice is neurogenic in origin: intracellular Cl- is elevated in vascular smooth muscle cells, but isolated arteries show no intrinsic vascular defect. Alpha1-adrenergic blockade or ganglionic transmission inhibition abolishes the blood pressure difference, and urinary catecholamines are elevated, demonstrating that elevated sympathetic tone mediates the hypertension. Vascular smooth muscle cell Cl- measurements, ex vivo vascular reactivity assays, in vivo pharmacological blockade, urinary catecholamine measurement in KCC3 knockout mice Circulation research High 16424367
2007 KCC3 is expressed in sciatic nerve during early postnatal development (juvenile but not adult wild-type mice). Loss of KCC3 causes initial axonal swelling at P3 (before myelin abnormalities), followed by periaxonal fluid accumulation, and ultimately axon and myelin degeneration in adults with reduced nerve conduction velocity, implicating cell volume regulation in peripheral nerve maintenance. KCC3 knockout mouse analysis, morphometric analysis of sciatic nerves at multiple postnatal timepoints, nerve conduction velocity measurement, immunohistochemistry Neurobiology of disease High 17659877
2007 IGF-1 upregulates KCC3 expression through PI3K and MAPK signaling cascades at the transcriptional level (blocked by actinomycin D), and KCC3-dependent transport is required for IGF-1-stimulated breast cancer cell proliferation. siRNA knockdown, KCC3 overexpression, pharmacological pathway inhibition, actinomycin D transcription block, xenograft tumor assay in SCID mice Journal of cellular physiology Medium 17133354
2012 Neuronal-specific KCC3 expression is crucial for axon volume control and accounts for the neuropathic features of HMSN/ACC, while loss of non-neuronal KCC3 causes auditory impairment. KCC3 also plays an essential role in inflammatory pain pathways. Conditional Cre/LoxP transgenic mice (neuron-specific and ubiquitous truncated KCC3 expression), behavioral, electrophysiological, and histological phenotyping The Journal of neuroscience High 22423107
2012 KCC3 contributes to Cl- extrusion in a subset of adult dorsal root ganglion sensory neurons, as demonstrated by gramicidin-perforated patch clamp in KCC3-/- mice showing failure of Cl- extrusion. Gramicidin-perforated patch-clamp recordings, quantitative RT-PCR, pharmacological inhibition with KCC cotransporter inhibitors in wild-type and KCC3-/- DRG neurons Molecular and cellular neurosciences High 22609694
2013 A glutamic acid residue (E289) is essential for proper trafficking and function of KCC3: the E289G mutation causes glycosylation deficiency, ER/early Golgi retention, and failure to reach the plasma membrane. This mutant KCC3 forms heterodimers with KCC2 (shown by co-immunoprecipitation) and exerts dominant-negative effects by preventing proper trafficking of co-expressed wild-type KCC cotransporters. Co-immunoprecipitation, glycosylation analysis, confocal microscopy of subcellular localization, functional assay in Xenopus oocytes PloS one High 23593405
2013 SPAK complexed with its regulatory MO25 subunit phosphorylates KCC3 at Ser-96 in vitro. In Xenopus oocytes, Ser-96 is phosphorylated under isotonic conditions and dephosphorylated during hypotonic conditions, contributing to full activation. WNK3 promotes phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. The triple mutant KCC3-S96A/T991A/T1048A has constitutive activity not further increased by hypotonicity or inhibited by WNK3. In vitro kinase assay with SPAK/MO25, site-directed mutagenesis, functional expression in Xenopus oocytes, HEK293 cells stably expressing WNK3 The Journal of biological chemistry High 24043619
2014 Loss of KCC3 specifically in parvalbumin-positive neurons leads to significant locomotor deficit in mice, identifying this cell population as critical for the pathogenic development of ACCPN. Loss of KCC3 in nociceptive neurons (Nav1.8-Cre) or Schwann cells (desert hedgehog-Cre) did not produce the locomotor phenotype. Tissue-specific KCC3 knockout mouse lines using Cre/loxP system (parvalbumin-Cre, NSE-Cre, Nav1.8-Cre, dhh-Cre), locomotor behavioral testing Behavioural brain research High 25116249
2014 KCC3 overexpression activates NF-κB and SPAK signaling, leading to p38 MAPK activation and MMP2 upregulation; SPAK is required for KCC3-mediated tumor cell invasiveness. NF-κB binds to the SPAK promoter in KCC3-overexpressing cells. siRNA knockdown, RT-PCR, NF-κB luciferase reporter assay, chromatin immunoprecipitation, gelatin zymography, mouse xenograft assay The FEBS journal Medium 24655550
2015 Phosphorylation of Thr-991 and Thr-1048 in the KCC3a C-terminus constitutes a potent molecular switch: alanine substitution at both sites (T991A/T1048A) activates KCC3a up to 25-fold under normally inhibitory isotonic conditions and is accompanied by reversal of NKCC1 activity, causing rapid and substantial reduction in intracellular K+ content via both Cl-dependent and Cl-independent (VRAC-sensitive) pathways. Site-directed mutagenesis (T991A/T1048A), ion transport assay, intracellular K+ measurement, pharmacological inhibition (DCPIB for VRAC, bumetanide for NKCC1) Frontiers in cellular neuroscience High 26217182
2016 A de novo T991A mutation in KCC3 abolishes WNK kinase-dependent phosphorylation at Thr-991, resulting in constitutive KCC3 activity and compromised cell volume homeostasis. KCC3-T991A/T1048A knock-in mice exhibit constitutive KCC3 activity and recapitulate clinical features of the patient's progressive motor peripheral neuropathy, demonstrating that over-activation of KCC3 causes neurodegeneration. Exome sequencing (patient identification), cell volume assay in patient cells, KCC3-T991A/T1048A knock-in mouse generation, electrophysiological and histopathological analysis Science signaling High 27485015
2019 Spleen tyrosine kinase (SYK) phosphorylates a specific N-terminal tyrosine residue of KCC3, and this phosphorylation decreases KCC3 abundance at the plasma membrane. SYK depletion or inhibition increases KCC3 membrane surface levels (opposite to its effect on NKCC2), linking tyrosine phosphorylation to differential regulation of cotransporter surface expression. SYK depletion (siRNA/pharmacological inhibitor), constitutively active SYK overexpression, plasma membrane abundance quantification in HEK cells Archives of biochemistry and biophysics Medium 31145900
2020 KCC3 knockout dorsal root ganglion neurons swell but fail to undergo regulatory volume decrease under hypotonic challenge, while neurons expressing constitutively active KCC3 show blunted swelling, directly demonstrating KCC3's integral role in cell volume homeostasis in sensory neurons. Wide-field microscopy with calcein fluorescence, cell volume measurements in DRG neurons from wild-type, KCC3 LOF, and KCC3 GOF mouse lines Cellular physiology and biochemistry High 32506846
2021 ZnR/GPR39 activation by Zn2+ recruits KCC3 into F-actin-rich membrane protrusions, promotes F-actin stress fiber formation, and activates MMP2 and MMP9 in a KCC3-dependent manner; KCC3 silencing reverses ZnR/GPR39-enhanced cell proliferation, migration, and invasion. KCC3 siRNA knockdown, immunofluorescence (KCC3 localization in protrusions), gelatin zymography (MMP2/MMP9), Matrigel invasion assay, ZnR/GPR39 activation Cell calcium Medium 33465674
2022 The KCC3a isoform is specifically expressed in type-B and non-A/non-B intercalated cells of the kidney connecting tubule (colocalizing with apical V-ATPase and pendrin), and its protein abundance is upregulated by metabolic alkalosis (NaHCO3), volume depletion (water restriction, low-salt diet), hydrochlorothiazide, amiloride, or K+-deficient diet. KCC3a-specific polyclonal antibody, immunofluorescence co-staining with cell-type markers (NCC, ENaC, calbindin, V-ATPase, pendrin), immunoblotting in wild-type and treated mice Frontiers in cell and developmental biology Medium 35874803
2023 Bicarbonate ion itself directly increases KCC3a protein abundance in type-B intercalated cells through a posttranscriptional mechanism (mRNA unchanged), independently of aldosterone, angiotensin II, or direct interaction with pendrin, as shown in wild-type and pendrin knockout mice. In vivo dietary NaHCO3/KHCO3 loading, immunoblotting, KCC3a abundance in pendrin knockout mice, in vitro bicarbonate treatment American journal of physiology. Cell physiology Medium 37036298
2021 Disrupting KCC3 expression in adult mice or re-expressing KCC3 in adult mice that developed without functional KCC3 has no effect on locomotor behavior, indicating that KCC3 function is critical specifically during embryonic/perinatal development and that the disease is irreversible once established. PV-CreERT2 tamoxifen-inducible system for temporal control of KCC3 deletion and re-expression; rotarod and gait behavioral testing American journal of physiology. Cell physiology Medium 33596149
2025 DCT-specific deletion of KCC3 reduces both total and phosphorylated NCC protein levels and NCC mRNA, indicating that KCC3 plays a role in basal regulation of NCC expression in the distal convoluted tubule, but KCC3 is not required for DCT adaptation to dietary K+ depletion. DCT-specific KCC3 conditional knockout mouse, immunoblotting for NCC and phospho-NCC, RT-qPCR for NCC mRNA, blood electrolyte measurements under standard and K+-deficient diet American journal of physiology. Renal physiology Medium 40875335
2025 A missense mutation p.H371R in SLC12A6 causes cytoplasmic mislocalization of the KCC3 protein (despite normal transcript and protein levels), disrupting ion transport function and leading to imbalanced intracellular K+ and Cl- levels and elevated cellular senescence markers (p16, p21). Functional analysis in patient cells: immunofluorescence for KCC3 subcellular localization, ion concentration measurement, Western blot for p16/p21, bioinformatics structural modeling Clinical genetics Medium 39988558

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. The Journal of biological chemistry 249 10347194
2002 The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nature genetics 217 12368912
2003 Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. The EMBO journal 177 14532115
1999 Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. The American journal of physiology 143 10600773
2001 Localization of the K(+)-Cl(-) cotransporter, KCC3, in the central and peripheral nervous systems: expression in the choroid plexus, large neurons and white matter tracts. Neuroscience 102 11246162
2001 The KCl cotransporter isoform KCC3 can play an important role in cell growth regulation. Proceedings of the National Academy of Sciences of the United States of America 76 11724933
2005 NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. American journal of physiology. Renal physiology 65 16048901
2007 Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice. Neurobiology of disease 64 17659877
2006 Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. Neurology 55 16606917
2016 Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. Science signaling 44 27485015
2006 Neurogenic mechanisms contribute to hypertension in mice with disruption of the K-Cl cotransporter KCC3. Circulation research 43 16424367
2013 N-terminal serine dephosphorylation is required for KCC3 cotransporter full activation by cell swelling. The Journal of biological chemistry 35 24043619
2007 IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness. Journal of cellular physiology 34 17133354
2003 Differential expression pattern of chloride transporters NCC, NKCC2, KCC1, KCC3, KCC4, and AE3 in the developing rat auditory brainstem. Cell and tissue research 34 12712325
2012 Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. The Journal of neuroscience : the official journal of the Society for Neuroscience 30 22423107
2008 Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 29 18536702
2015 Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis. Frontiers in cellular neuroscience 25 26217182
2013 A trafficking-deficient mutant of KCC3 reveals dominant-negative effects on K-Cl cotransport function. PloS one 25 23593405
2006 KCC3 and KCC4 expression in rat adult forebrain. Brain research 25 16872584
2014 Deletion of KCC3 in parvalbumin neurons leads to locomotor deficit in a conditional mouse model of peripheral neuropathy associated with agenesis of the corpus callosum. Behavioural brain research 24 25116249
2003 The NO signaling pathway differentially regulates KCC3a and KCC3b mRNA expression. Nitric oxide : biology and chemistry 23 14732340
2007 Distal truncation of KCC3 in non-French Canadian HMSN/ACC families. Neurology 21 17893295
2018 A role for KCC3 in maintaining cell volume of peripheral nerve fibers. Neurochemistry international 19 29366908
2012 KCC3-dependent chloride extrusion in adult sensory neurons. Molecular and cellular neurosciences 19 22609694
2014 SPAK mediates KCC3-enhanced cervical cancer tumorigenesis. The FEBS journal 17 24655550
2010 Cellular expression of the K+-Cl- cotransporter KCC3 in the central nervous system of mouse. Brain research 17 21147077
2001 Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy. Epilepsy research 17 11325574
2009 Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene. Neuropediatrics 16 20020398
2022 KCC3a, a Strong Candidate Pathway for K+ Loss in Alkalemia. Frontiers in cell and developmental biology 15 35874803
2024 Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing. Cell reports 13 38421867
2012 High-grade glioma motility reduced by genetic knockdown of KCC3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 12 22776998
2023 Bicarbonate is the primary inducer of KCC3a expression in renal cortical B-type intercalated cells. American journal of physiology. Cell physiology 9 37036298
2021 ZnR/GPR39 controls cell migration by orchestrating recruitment of KCC3 into protrusions, re-organization of actin and activation of MMP. Cell calcium 8 33465674
2016 KCC3 axonopathy: neuropathological features in the central and peripheral nervous system. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 8 27230413
2019 Tyrosine phosphorylation modulates cell surface expression of chloride cotransporters NKCC2 and KCC3. Archives of biochemistry and biophysics 7 31145900
2008 A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice. Genomics 7 18343091
2023 Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype. Brain : a journal of neurology 6 36542484
2022 Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease. Annals of clinical and translational neurology 5 35733399
2020 Osmotic Response of Dorsal Root Ganglion Neurons Expressing Wild-Type and Mutant KCC3 Transporters. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 32506846
2020 Whole-exome sequencing identifies a heterozygous mutation in SLC12A6 associated with hereditary sensory and motor neuropathy. Neuromuscular disorders : NMD 5 33323309
2021 Expanding the phenotype of SLC12A6-associated sensorimotor neuropathy. BMJ case reports 4 34706912
2020 A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum. Journal of pediatric genetics 4 32765936
2022 Erythroid-specific inactivation of Slc12a6/Kcc3 by EpoR promoter-driven Cre expression reduces K-Cl cotransport activity in mouse erythrocytes. Physiological reports 3 35274823
2019 First case of Roma ethnic origin with Andermann syndrome: A novel frameshift mutation in exon 20 of SLC12A6 gene. American journal of medical genetics. Part A 3 30868738
2021 Temporal manipulation of KCC3 expression in juvenile or adult mice suggests irreversible developmental deficit in hereditary motor sensory neuropathy with agenesis of the corpus callosum. American journal of physiology. Cell physiology 2 33596149
2026 Spectrum of dominant Charcot-Marie-Tooth disease due to SLC12A6 variants. Journal of neurology, neurosurgery, and psychiatry 1 41500801
2025 A "Knob Switch" Model for the Phosphoregulatory Mechanism of KCC3 at the Carboxy-Terminal Domain. Biochemistry 1 40009635
2025 A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy. Clinical genetics 0 39988558
2025 KCC3 is not required for the distal convoluted tubule response to reduced dietary potassium intake. American journal of physiology. Renal physiology 0 40875335

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