Gene Symbol: KCC3
Description: solute carrier family 12 member 6
Alias: ACCPN, KCC3, KCC3A, KCC3B, solute carrier family 12 member 6, K-Cl cotransporter 3, electroneutral potassium-chloride cotransporter 3, potassium chloride cotransporter 3, potassium chloride cotransporter KCC3a-S3, potassium-chloride transporter-3a, potassium-chloride transporter-3b, solute carrier family 12 (potassium/chloride transporter), member 6, solute carrier family 12 (potassium/chloride transporters), member 6
Species: human
Products:     KCC3

Top Publications

  1. Race J, Makhlouf F, Logue P, Wilson F, Dunham P, Holtzman E. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Am J Physiol. 1999;277:C1210-9 pubmed
    We isolated and characterized a novel K-Cl cotransporter, KCC3, from human placenta. The deduced protein contains 1,150 amino acids...
  2. Mercado A, Vazquez N, Song L, Cortés R, Enck A, Welch R, et al. NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Am J Physiol Renal Physiol. 2005;289:F1246-61 pubmed
    ..Two major isoforms, KCC3a and KCC3b, are generated by transcriptional initiation 5' of two distinct first coding exons...
  3. Cruz Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla N, Pasantes Morales H, et al. Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol. 2011;301:C601-8 pubmed publisher
    ..That is, NKCC1/2 and NCC were inhibited, even in hypertonicity, while KCCs were activated, even in isotonic conditions. We conclude that the effects of all WNK3 variants toward SLC12 proteins are similar. ..
  4. Howard H, Mount D, Rochefort D, Byun N, Dupre N, Lu J, et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002;32:384-92 pubmed
    Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum...
  5. Mount D, Mercado A, Song L, Xu J, George A, Delpire E, et al. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J Biol Chem. 1999;274:16355-62 pubmed
    ..We have cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members of this gene family...
  6. Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem. 2002;277:50812-9 pubmed
    ..Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) with the cotransporters KCC3, NKCC1, and NKCC2 but not KCC1 and KCC4...
  7. Melo Z, de los Heros P, Cruz Rangel S, Vazquez N, Bobadilla N, Pasantes Morales H, et al. N-terminal serine dephosphorylation is required for KCC3 cotransporter full activation by cell swelling. J Biol Chem. 2013;288:31468-76 pubmed publisher
    ..Two phosphorylation sites (Thr-991 and Thr-1048) in KCC3 have been found to be critical for its regulation...
  8. Hsu Y, Chen Y, Chou C, Tang M, Chen J, Wilkins R, et al. KCl cotransporter-3 down-regulates E-cadherin/beta-catenin complex to promote epithelial-mesenchymal transition. Cancer Res. 2007;67:11064-73 pubmed
    ..Real-time reverse transcription-PCR on the samples collected from the laser microdissection indicates that KCC3 is the most abundant KCC isoform in cervical carcinoma...
  9. Hsu Y, Chou C, Chen H, Lee W, Chen Y, Lin P, et al. IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness. J Cell Physiol. 2007;210:626-36 pubmed
    ..IGF-1 stimulates KCC activity of MCF-7 breast cancer cells in a dose- and time-dependent manner. Increased KCC3 and KCC4 abundances contribute to IGF-1-enhanced KCC activity...

More Information


  1. Salin Cantegrel A, Rivière J, Shekarabi M, Rasheed S, Dacal S, Laganiere J, et al. Transit defect of potassium-chloride Co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum. J Biol Chem. 2011;286:28456-65 pubmed publisher
    Missense and protein-truncating mutations of the human potassium-chloride co-transporter 3 gene (KCC3) cause hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), which is a severe neurodegenerative ..
  2. Rinehart J, Maksimova Y, Tanis J, Stone K, Hodson C, Zhang J, et al. Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell. 2009;138:525-36 pubmed publisher
    ..We identified two sites in KCC3 that are rapidly dephosphorylated in hypotonic conditions in cultured cells and human red blood cells in parallel ..
  3. Uyanik G, Elcioglu N, Penzien J, Gross C, Yilmaz Y, Olmez A, et al. Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. Neurology. 2006;66:1044-8 pubmed
    ..Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome...
  4. Ding J, Delpire E. 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. Behav Brain Res. 2014;274:128-36 pubmed publisher
    Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC or ACCPN) is an autosomal recessive disease caused by the disruption of the SLC12A6 gene, which encodes the K-Cl cotransporter-3 (KCC3)...
  5. Sun Y, Tzeng S, Lin T, Hsu K, Delpire E, Shen M. KCC3 deficiency-induced disruption of paranodal loops and impairment of axonal excitability in the peripheral nervous system. Neuroscience. 2016;335:91-102 pubmed publisher
    ..of the Corpus Callosum (HMSN/ACC) is associated with the dysfunction of the K(+)-Cl(-) cotransporter type 3 (KCC3), which is an electroneutral cotransporter...
  6. Kahle K, Khanna A, Alper S, Adragna N, Lauf P, Sun D, et al. K-Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med. 2015;21:513-23 pubmed publisher
    ..Genetic models of certain KCCs, such as KCC3, and their inhibitory WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK) serine-threonine kinases, have ..
  7. Zhang J, Gao G, Begum G, Wang J, Khanna A, Shmukler B, et al. Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain. Sci Rep. 2016;6:35986 pubmed publisher
    ..and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr991/Thr1048 phosphorylation - a key signaling event in cell swelling-induced regulatory ..
  8. Wilms V, Söffgen C, Nothwang H. Differences in molecular mechanisms of K+ clearance in the auditory sensory epithelium of birds and mammals. J Exp Biol. 2017;220:2701-2705 pubmed publisher
    ..Marked differences were observed for K+ clearance. In mammals, KCC3, KCC4, Kir4.1 and CLC-K are present in supporting cells...
  9. Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73-85 pubmed publisher
    ..Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease. ..
  10. Adragna N, Ravilla N, Lauf P, Begum G, Khanna A, Sun D, et al. Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis. Front Cell Neurosci. 2015;9:255 pubmed publisher
    ..Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-..
  11. Bowerman M, Salsac C, Bernard V, Soulard C, Dionne A, Coque E, et al. KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects. Neurobiol Dis. 2017;106:35-48 pubmed publisher
    Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities...
  12. Merner N, Mercado A, Khanna A, Hodgkinson A, Bruat V, Awadalla P, et al. Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. J Psychiatr Res. 2016;77:22-6 pubmed publisher
    ..No NKCC1 variants were detected in ASD or ID, and no KCC3 variants were identified in any of the three neurodevelopmental disorder cohorts...
  13. Dong J, Levine D, Buas M, Zhang R, Onstad L, Fitzgerald R, et al. Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus. Clin Gastroenterol Hepatol. 2018;16:1598-1606.e4 pubmed publisher
    ..82×10-7), respectively. The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted. ..
  14. Flores B, Schornak C, Delpire E. A role for KCC3 in maintaining cell volume of peripheral nerve fibers. Neurochem Int. 2019;123:114-124 pubmed publisher
    The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the peripheral and central nervous system...
  15. Garneau A, Marcoux A, Noël M, Frenette Cotton R, Drolet M, Couet J, et al. Ablation of Potassium-Chloride Cotransporter Type 3 (Kcc3) in Mouse Causes Multiple Cardiovascular Defects and Isosmotic Polyuria. PLoS ONE. 2016;11:e0154398 pubmed publisher
    Inactivation of Kcc3 in a mixed 129/Sv×C57BL/6 mouse background has been previously found to increase systemic blood pressure (BP) through presumed neurogenic mechanisms...
  16. Bazúa Valenti S, Castañeda Bueno M, Gamba G. Physiological role of SLC12 family members in the kidney. Am J Physiol Renal Physiol. 2016;311:F131-44 pubmed publisher
    ..The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but ..
  17. Bergeron M, Gagnon E, Wallendorff B, Lapointe J, Isenring P. Ammonium transport and pH regulation by K(+)-Cl(-) cotransporters. Am J Physiol Renal Physiol. 2003;285:F68-78 pubmed
    ..Our results demonstrate that all of the CCCs examined (NKCC1, NKCC2, KCC1, KCC3, and KCC4) can promote NH4(+) translocation, presumably through binding of the ion at the K(+) site...
  18. Garneau A, Marcoux A, Frenette Cotton R, Mac Way F, Lavoie J, Isenring P. Molecular insights into the normal operation, regulation, and multisystemic roles of K+-Cl- cotransporter 3 (KCC3). Am J Physiol Cell Physiol. 2017;313:C516-C532 pubmed publisher
    ..It was termed KCC1 and led to the discovery of three isoforms called KCC2, KCC3, and KCC4...
  19. de los Heros P, Alessi D, Gourlay R, Campbell D, Deak M, MacArtney T, et al. The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J. 2014;458:559-73 pubmed publisher
    ..Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency...
  20. Shen M, Lin A, Hsu Y, Chang T, Tang M, Alper S, et al. Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells. J Biol Chem. 2004;279:40017-25 pubmed
    ..Taken together, our results indicate that KCC activation by IGF-1 plays an important role in IGF-1 signaling to promote growth and spread of gynecological cancers. ..
  21. Auer R, Laganière J, Robitaille Y, Richardson J, Dion P, Rouleau G, et al. KCC3 axonopathy: neuropathological features in the central and peripheral nervous system. Mod Pathol. 2016;29:962-76 pubmed publisher
    ..deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.
  22. Moser D, Ekawardhani S, Kumsta R, Palmason H, Bock C, Athanassiadou Z, et al. Functional analysis of a potassium-chloride co-transporter 3 (SLC12A6) promoter polymorphism leading to an additional DNA methylation site. Neuropsychopharmacology. 2009;34:458-67 pubmed publisher
    The human potassium-chloride co-transporter 3 (KCC3, SLC12A6) is involved in cell proliferation and in electro-neutral movement of ions across the cell membrane...
  23. Hiki K, D Andrea R, Furze J, Crawford J, Woollatt E, Sutherland G, et al. Cloning, characterization, and chromosomal location of a novel human K+-Cl- cotransporter. J Biol Chem. 1999;274:10661-7 pubmed
    ..We have referred to the predicted protein as K+-Cl- cotransporter 3 (KCC3)...
  24. Meyer J, Johannssen K, Freitag C, Schraut K, Teuber I, Hahner A, et al. Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. Int J Neuropsychopharmacol. 2005;8:495-504 pubmed
    ..cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN)...
  25. Chiu M, Liu H, Wu Y, Shen M, Chou C. SPAK mediates KCC3-enhanced cervical cancer tumorigenesis. FEBS J. 2014;281:2353-65 pubmed publisher
    ..kinase (SPAK) plays a role in regulating many biological activities, and interacts with K-Cl co-transporter 3 (KCC3); however, the importance of SPAK for KCC3 function has not been demonstrated...
  26. Salin Cantegrel A, Shekarabi M, Holbert S, Dion P, Rochefort D, Laganiere J, et al. HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3. Hum Mol Genet. 2008;17:2703-11 pubmed publisher
    The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in ..
  27. Rudnik Schoneborn S, Hehr U, von Kalle T, Bornemann A, Winkler J, Zerres K. 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. 2009;40:129-33 pubmed publisher
    ..Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p...
  28. Kahle K, Flores B, Bharucha Goebel D, Zhang J, Donkervoort S, Hegde M, et al. Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. Sci Signal. 2016;9:ra77 pubmed publisher
    ..2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons...
  29. Foote J, Behe P, Frampton M, Levine A, Segal A. An Exploration of Charge Compensating Ion Channels across the Phagocytic Vacuole of Neutrophils. Front Pharmacol. 2017;8:94 pubmed publisher
    ..to identify specific channels, we tested neutrophils from knock-out mouse models including CLIC1, ClC3, ClC4, ClC7, KCC3, KCNQ1, KCNE3, KCNJ15, TRPC1/3/5/6, TRPA1/TRPV1, TRPM2, and TRPV2, and double knockouts of CLIC1, ClC3, KCC3, TRPM2,..
  30. Casula S, Shmukler B, Wilhelm S, Stuart Tilley A, Su W, Chernova M, et al. A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem. 2001;276:41870-8 pubmed
    ..Delta(N)117 also exhibited dominant negative inhibition of human KCC1 and KCC3 and, with lower potency, mouse KCC4 and rat KCC2.
  31. Degerliyurt A, Akgumus G, Caglar C, Bilguvar K, Caglayan A. A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity?. Genet Couns. 2013;24:283-9 pubmed
    ..is an autosomal recessive disorder characterized by the agenesis of the corpus callosum and peripheral neuropathy (ACCPN)...
  32. Shekarabi M, Moldrich R, Rasheed S, Salin Cantegrel A, Laganiere J, Rochefort D, et al. 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. J Neurosci. 2012;32:3865-76 pubmed publisher
    Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and ..
  33. Salin Cantegrel A, Riviere J, Dupre N, Charron F, Shekarabi M, Karemera L, et al. Distal truncation of KCC3 in non-French Canadian HMSN/ACC families. Neurology. 2007;69:1350-5 pubmed
    ..Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population...
  34. Bräuer M, Frei E, Claes L, Grissmer S, Jäger H. Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts. Am J Physiol Cell Physiol. 2003;285:C22-30 pubmed
  35. Shiozaki A, Takemoto K, Ichikawa D, Fujiwara H, Konishi H, Kosuga T, et al. The K-Cl cotransporter KCC3 as an independent prognostic factor in human esophageal squamous cell carcinoma. Biomed Res Int. 2014;2014:936401 pubmed publisher
    The objectives of the present study were to investigate the role of K-Cl cotransporter 3 (KCC3) in the regulation of cellular invasion and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC)...
  36. Pan D, Kalfa T, Wang D, Risinger M, Crable S, Ottlinger A, et al. K-Cl cotransporter gene expression during human and murine erythroid differentiation. J Biol Chem. 2011;286:30492-503 pubmed publisher
    ..Message levels for KCC1 and KCC3b were low. The ratios of KCC RNA levels varied among individuals but were similar in sickle and normal RBC...