Gene Symbol: Slc12a2
Description: solute carrier family 12, member 2
Alias: 9330166H04Rik, Nkcc1, mBSC2, sy-ns, solute carrier family 12 member 2, basolateral Na-K-Cl symporter, bumetanide-sensitive sodium-(potassium)-chloride cotransporter 1, sodium/potassium/chloride cotransporters, sodium/potassium/chloride transporters
Species: mouse
Products:     Slc12a2

Top Publications

  1. Meyer J, Flagella M, Sutliff R, Lorenz J, Nieman M, Weber C, et al. Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na(+)-K(+)-2Cl(-) cotransporter. Am J Physiol Heart Circ Physiol. 2002;283:H1846-55 pubmed
    The basolateral Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) functions in the maintenance of cellular electrolyte and volume homeostasis...
  2. Sipilä S, Huttu K, Yamada J, Afzalov R, Voipio J, Blaesse P, et al. Compensatory enhancement of intrinsic spiking upon NKCC1 disruption in neonatal hippocampus. J Neurosci. 2009;29:6982-8 pubmed publisher
    ..We show here that GABA has no excitatory action on CA3 pyramidal neurons in hippocampal slices from neonatal NKCC1(-/-) mice that lack the Na-K-2Cl cotransporter isoform 1...
  3. Pace A, Madden V, Henson O, Koller B, Henson M. Ultrastructure of the inner ear of NKCC1-deficient mice. Hear Res. 2001;156:17-30 pubmed
    ..We have generated mice deficient in NKCC1, an ion cotransporter that is thought to be involved in the secretion of K+ by the strial marginal cells...
  4. Grubb B, Pace A, Lee E, Koller B, Boucher R. Alterations in airway ion transport in NKCC1-deficient mice. Am J Physiol Cell Physiol. 2001;281:C615-23 pubmed
    Airways of Na(+)-K(+)-2Cl(-) (NKCC1)-deficient mice (-/-) were studied in Ussing chambers to determine the role of the basolateral NKCC1 in transepithelial anion secretion...
  5. Hengl T, Kaneko H, Dauner K, Vocke K, Frings S, Möhrlen F. Molecular components of signal amplification in olfactory sensory cilia. Proc Natl Acad Sci U S A. 2010;107:6052-7 pubmed publisher
    ..We found that the Na(+)/K(+)/2Cl(-) cotransporter NKCC1 is expressed in the ciliary membrane, where it mediates chloride accumulation into the ciliary lumen...
  6. Dixon M, Gazzard J, Chaudhry S, Sampson N, Schulte B, Steel K. Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice. Hum Mol Genet. 1999;8:1579-84 pubmed
    ..candidate approach, we demonstrate that mutations in the gene encoding the basolateral Na-K-Cl co-transporter Slc12a2 (Nkcc1, mBSC2) cause the deafness observed in sy and sy(ns) mice...
  7. Blaesse P, Airaksinen M, Rivera C, Kaila K. Cation-chloride cotransporters and neuronal function. Neuron. 2009;61:820-38 pubmed publisher
    ..The rapidly expanding work on CCCs promotes our understanding of fundamental mechanisms that control brain development and functions under normal and pathophysiological conditions. ..
  8. Dzhala V, KUCHIBHOTLA K, Glykys J, Kahle K, Swiercz W, Feng G, et al. Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures. J Neurosci. 2010;30:11745-61 pubmed publisher
    ..The Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter blocker bumetanide inhibited seizure-induced neuronal Cl(-) accumulation and the consequent ..
  9. Delpy A, Allain A, Meyrand P, Branchereau P. NKCC1 cotransporter inactivation underlies embryonic development of chloride-mediated inhibition in mouse spinal motoneuron. J Physiol. 2008;586:1059-75 pubmed
    ..turns to inhibition due to modification of the chloride equilibrium potential (E(Cl)) controlled by the KCC2 and NKCC1 transporters...

More Information


  1. Pace A, Lee E, Athirakul K, Coffman T, O Brien D, Koller B. Failure of spermatogenesis in mouse lines deficient in the Na(+)-K(+)-2Cl(-) cotransporter. J Clin Invest. 2000;105:441-50 pubmed
    ..We have generated mouse lines carrying either of 2 mutant alleles of the Slc12a2 gene, which encodes this cotransporter: a null allele and a mutation that results in deletion of 72 amino acids ..
  2. Delpire E, Rauchman M, Beier D, Hebert S, Gullans S. Molecular cloning and chromosome localization of a putative basolateral Na(+)-K(+)-2Cl- cotransporter from mouse inner medullary collecting duct (mIMCD-3) cells. J Biol Chem. 1994;269:25677-83 pubmed
    ..Sequence comparison and chromosome localization demonstrate that BSC2 and BSC1 are different genes that diverged before the evolution of vertebrates. ..
  3. Nickell W, Kleene N, Kleene S. Mechanisms of neuronal chloride accumulation in intact mouse olfactory epithelium. J Physiol. 2007;583:1005-20 pubmed
    ..In isolated olfactory receptor neurons, the Na(+)-K(+)-2Cl(-) cotransporter NKCC1 is essential for Cl(-) accumulation...
  4. Ge S, Goh E, Sailor K, Kitabatake Y, Ming G, Song H. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439:589-93 pubmed
  5. Reisert J, Lai J, Yau K, Bradley J. Mechanism of the excitatory Cl- response in mouse olfactory receptor neurons. Neuron. 2005;45:553-61 pubmed
    ..We show here that a (Na+)-(K+)-(2Cl-) cotransporter, NKCC1, is required for this Cl- current, in that ORNs deficient in Nkcc1 or incubated with an NKCC blocker (bumetanide) ..
  6. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999;22:192-5 pubmed
    ..called NKCC2, encoded by Slc12a1 in mouse) that is exclusively expressed in kidney; and BSC2/NKCC1 (encoded by Slc12a2 in mouse), the secretory isoform which has a wider pattern of expression including epithelia, muscle cells, ..
  7. Flagella M, Clarke L, Miller M, Erway L, Giannella R, Andringa A, et al. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946-55 pubmed
    In chloride-secretory epithelia, the basolateral Na-K-2Cl cotransporter (NKCC1) is thought to play a major role in transepithelial Cl(-) and fluid transport...
  8. Sung K, Kirby M, McDonald M, Lovinger D, Delpire E. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci. 2000;20:7531-8 pubmed
    We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999)...
  9. Wang D, Kriegstein A. GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci. 2008;28:5547-58 pubmed publisher
    ..neurotransmitter in adults, excites neurons as a result of high expression of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1)...
  10. Kim H, Wangemann P. Epithelial cell stretching and luminal acidification lead to a retarded development of stria vascularis and deafness in mice lacking pendrin. PLoS ONE. 2011;6:e17949 pubmed publisher
  11. Lin S, Yu I, Jiang S, Lin S, Chu P, Chen A, et al. Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome. Proc Natl Acad Sci U S A. 2011;108:17538-43 pubmed publisher
    Na(+)-K(+)-2Cl(-) cotransporters (NKCCs), including NKCC1 and renal-specific NKCC2, and the Na(+)-Cl(-) cotransporter (NCC) play pivotal roles in the regulation of blood pressure (BP) and renal NaCl reabsorption...
  12. Li X, Zhou J, Chen Z, Chen S, Zhu F, Zhou L. Long-term expressional changes of Na+ -K+ -Cl- co-transporter 1 (NKCC1) and K+ -Cl- co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE). Brain Res. 2008;1221:141-6 pubmed publisher
    b>NKCC1 and KCC2 are encoded by slc12 gene family and involved in the maintenance of intracellular chloride concentration which may be associated with epileptogenesis...
  13. Cutler C, Cramb G. Two isoforms of the Na+/K+/2Cl- cotransporter are expressed in the European eel (Anguilla anguilla). Biochim Biophys Acta. 2002;1566:92-103 pubmed
    Two cDNA isoforms of the NKCC1 secretory cotransporter have been isolated from the European eel...
  14. Rasmussen L, Müller H, Jørgensen B, Pedersen S, Hoffmann E. Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells. Am J Physiol Cell Physiol. 2015;308:C101-10 pubmed publisher
    ..Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 ..
  15. Ip W, Medzhitov R. Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation. Nat Commun. 2015;6:6931 pubmed publisher
    ..Our findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response. ..
  16. Hoffmann E, Pedersen S. Shrinkage insensitivity of NKCC1 in myosin II-depleted cytoplasts from Ehrlich ascites tumor cells. Am J Physiol Cell Physiol. 2007;292:C1854-66 pubmed
    ..phosphorylation/dephosphorylation and cytoskeletal reorganization regulate the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) during osmotic shrinkage; however, the mechanisms involved are unclear...
  17. Chen X, Kintner D, Luo J, Baba A, Matsuda T, Sun D. Endoplasmic reticulum Ca2+ dysregulation and endoplasmic reticulum stress following in vitro neuronal ischemia: role of Na+-K+-Cl- cotransporter. J Neurochem. 2008;106:1563-76 pubmed publisher
    We investigated the role of Na(+)-K(+)-Cl(-) cotransporter (NKCC1) in conjunction with Na(+)/Ca(2+) exchanger (NCX) in disruption of endoplasmic reticulum (ER) Ca(2+) homeostasis and ER stress development in primary cortical neurons ..
  18. Gagnon K, Delpire E. Molecular determinants of hyperosmotically activated NKCC1-mediated K+/K+ exchange. J Physiol. 2010;588:3385-96 pubmed publisher
    ..Under isosmotic conditions or with activation of the kinases SPAK/WNK4, the NKCC1-mediated Cl(-) uptake in Xenopus laevis oocytes, as measured using (36)Cl, is twice the value of K(+) uptake, as ..
  19. Antoine M, Hübner C, Arezzo J, Hebert J. A causative link between inner ear defects and long-term striatal dysfunction. Science. 2013;341:1120-3 pubmed publisher
    ..Using molecular and behavioral assessments of mice that carry null or tissue-specific mutations of Slc12a2, we found that inner ear dysfunction causes motor hyperactivity by increasing in the nucleus accumbens the levels ..
  20. Hui H, Rao W, Zhang L, Xie Z, Peng C, Su N, et al. Inhibition of Na(+)-K(+)-2Cl(-) Cotransporter-1 attenuates traumatic brain injury-induced neuronal apoptosis via regulation of Erk signaling. Neurochem Int. 2016;94:23-31 pubmed publisher
    ..This study aimed to investigate the role of the Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) in the disruption of ion homeostasis and neuronal apoptosis in TBI...
  21. Chu H, Xiong H, Han F, Wu Z, Huang X, Cui Y. [Association of age-related hearing loss with mice which expressed only one copy of gene encoding NKCC1 co-transporter]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2006;41:537-41 pubmed
    To generate transgenic mice of NKCC1 +/- (heterozygous) and NKCC1 +/+ (wild-type) that have a targeted disruption in the NKCC1 gene in order to investigate the relationship of one copy of NKCC1 gene (NKCC1 +/-) and age-related hearing ..
  22. Bergaya S, Faure S, Baudrie V, Rio M, Escoubet B, Bonnin P, et al. WNK1 regulates vasoconstriction and blood pressure response to ? 1-adrenergic stimulation in mice. Hypertension. 2011;58:439-45 pubmed publisher
    ..phosphorylation level of the WNK1 substrate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and its target NKCC1 (Na(+)-K(+)-2Cl(-) cotransporter 1) in Wnk1(+/-) arteries...
  23. Schöbel N, Radtke D, Lübbert M, Gisselmann G, Lehmann R, Cichy A, et al. Trigeminal ganglion neurons of mice show intracellular chloride accumulation and chloride-dependent amplification of capsaicin-induced responses. PLoS ONE. 2012;7:e48005 pubmed publisher
    ..DRG) and olfactory sensory neurons (OSNs), Cl(-) is accumulated by the Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1), resulting in a [Cl(-)](i) above electrochemical equilibrium and a depolarizing Cl(-) efflux upon Cl(-) channel ..
  24. Khirug S, Yamada J, Afzalov R, Voipio J, Khiroug L, Kaila K. GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1. J Neurosci. 2008;28:4635-9 pubmed publisher
    ..Data from NKCC1(-/-) and bumetanide-exposed neurons indicated that the depolarizing E(GABA) at the AIS is set by chloride uptake ..
  25. Jantzie L, Hu M, Park H, Jackson M, Yu J, Maxwell J, et al. Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia. Pediatr Res. 2015;77:554-62 pubmed publisher
    Periventricular leukomalacia (PVL) is a major form of preterm brain injury. Na(+)-K(+)-Cl(-) 1 cotransporter (NKCC1) expression on neurons and astrocytes is developmentally regulated and mediates Cl(-) reversal potential...
  26. Castrop H, Lorenz J, Hansen P, Friis U, Mizel D, Oppermann M, et al. Contribution of the basolateral isoform of the Na-K-2Cl- cotransporter (NKCC1/BSC2) to renin secretion. Am J Physiol Renal Physiol. 2005;289:F1185-92 pubmed
    ..However, loop diuretics also inhibit NKCC1, the second isoform of the Na-K-2Cl cotransporter, with similar potency...
  27. Prasad V, Bodi I, Meyer J, Wang Y, Ashraf M, Engle S, et al. Impaired cardiac contractility in mice lacking both the AE3 Cl-/HCO3- exchanger and the NKCC1 Na+-K+-2Cl- cotransporter: effects on Ca2+ handling and protein phosphatases. J Biol Chem. 2008;283:31303-14 pubmed publisher
    ..The NKCC1 Na+-K+-2Cl(-) cotransporter also mediates Na+ uptake, and loss of NKCC1 alone does not impair contractility...
  28. Gawenis L, Hut H, Bot A, Shull G, de Jonge H, Stien X, et al. Electroneutral sodium absorption and electrogenic anion secretion across murine small intestine are regulated in parallel. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1140-9 pubmed
    ..e., CFTR-null [CFTR(-)] or Na(+)-K(+)-2Cl(-) cotransporter-null [NKCC1(-)]. Protein expression of NHE3 and CFTR in the intestinal epithelia was measured by immunoblotting...
  29. Yousuf M, Zubkow K, Tenorio G, Kerr B. The chloride co-transporters, NKCC1 and KCC2, in experimental autoimmune encephalomyelitis (EAE). Neuroscience. 2017;344:178-186 pubmed publisher
    ..Na+-K+-2Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) generally dictate the tone of GABA/glycine inhibition by regulating ..
  30. Miller M, Judd L, van Driel I, Andringa A, Flagella M, Bell S, et al. The unique ultrastructure of secretory membranes in gastric parietal cells depends upon the presence of H+, K+ -ATPase. Cell Tissue Res. 2002;309:369-80 pubmed
    ..In mice lacking Na+/H+ exchanger 1 (NHE1) or the Na+-K+-2Cl- cotransporter (NKCC1), the ultrastructure and Vd of secretory membranes and the secretory canalicular to tubulovesicular membrane ratio ..
  31. Delpire E, Gagnon K. Kinetics of hyperosmotically stimulated Na-K-2Cl cotransporter in Xenopus laevis oocytes. Am J Physiol Cell Physiol. 2011;301:C1074-85 pubmed publisher
    A detailed study of hypertonically stimulated Na-K-2Cl cotransport (NKCC1) in Xenopus laevis oocytes was carried out to better understand the 1 K(+):1 Cl(-) stoichiometry of transport that was previously observed...
  32. Alshahrani S, Almutairi M, Kursan S, Dias Junior E, Almiahuob M, Aguilar Bryan L, et al. Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice. J Endocrinol. 2015;227:153-65 pubmed publisher
    The products of the Slc12a1 and Slc12a2 genes, commonly known as Na(+)-dependent K(+)2Cl(-) co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide...
  33. Shulga A, Magalhães A, Autio H, Plantman S, Di Lieto A, Nykjær A, et al. The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons. J Neurosci. 2012;32:1757-70 pubmed publisher
    ..Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF. ..
  34. Tsukahara T, Masuhara M, Iwai H, Sonomura T, Sato T. Repeated stress-induced expression pattern alterations of the hippocampal chloride transporters KCC2 and NKCC1 associated with behavioral abnormalities in female mice. Biochem Biophys Res Commun. 2015;465:145-51 pubmed publisher
    The balance of cation-chloride co-transporters, particularly KCC2 and NKCC1, is critical for GABAergic inhibitory signaling. However, KCC2/NKCC1 balance is disrupted in many neurodegenerative diseases...
  35. Chen H, Luo J, Kintner D, Shull G, Sun D. Na(+)-dependent chloride transporter (NKCC1)-null mice exhibit less gray and white matter damage after focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25:54-66 pubmed
    We previously demonstrated that pharmacological inhibition of Na(+)-K(+)-Cl- cotransporter isoform 1 (NKCC1) is neuroprotective in in vivo and in vitro ischemic models...
  36. Zhang L, Delpire E, Vardi N. NKCC1 does not accumulate chloride in developing retinal neurons. J Neurophysiol. 2007;98:266-77 pubmed
    ..This initial high concentration is commonly attributed to the ubiquitous chloride cotransporter NKCC1, which uses a sodium gradient to accumulate chloride...
  37. Wall S, Knepper M, Hassell K, Fischer M, Shodeinde A, Shin W, et al. Hypotension in NKCC1 null mice: role of the kidneys. Am J Physiol Renal Physiol. 2006;290:F409-16 pubmed
    b>NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored...
  38. Haering C, Kanageswaran N, Bouvain P, Scholz P, Altmüller J, Becker C, et al. Ion transporter NKCC1, modulator of neurogenesis in murine olfactory neurons. J Biol Chem. 2015;290:9767-79 pubmed publisher
    ..In recent years, the precise role of the ion transporter NKCC1 in olfactory sensory neuron (OSN) chloride accumulation has been a controversial subject...
  39. Johnson K, Cook S, Zheng Q. The original shaker-with-syndactylism mutation (sy) is a contiguous gene deletion syndrome. Mamm Genome. 1998;9:889-92 pubmed
    ..The genetic relationships described here will aid in positional cloning efforts to identify the genes responsible for the disparate phenotypes associated with the sy locus...
  40. Kakizawa K, Watanabe M, Mutoh H, Okawa Y, Yamashita M, Yanagawa Y, et al. A novel GABA-mediated corticotropin-releasing hormone secretory mechanism in the median eminence. Sci Adv. 2016;2:e1501723 pubmed publisher
    ..The GABAA receptor (GABAAR) and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1), but not the K(+)-Cl(-) cotransporter (KCC2), were expressed in the terminals of the CRH neurons at the median ..
  41. Kim S, Eisner C, Faulhaber Walter R, Mizel D, Wall S, Briggs J, et al. Salt sensitivity of blood pressure in NKCC1-deficient mice. Am J Physiol Renal Physiol. 2008;295:F1230-8 pubmed publisher
    b>NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin...
  42. Köchl R, Thelen F, Vanes L, Brazão T, Fountain K, Xie J, et al. WNK1 kinase balances T cell adhesion versus migration in vivo. Nat Immunol. 2016;17:1075-83 pubmed publisher
    ..whereas it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2. WNK1-deficient T cells home less efficiently to lymphoid organs and migrate more slowly through them...
  43. Srivastava U, Paigen B, Korstanje R. Differences in health status affect susceptibility and mapping of genetic loci for atherosclerosis (fatty streak) in inbred mice. Arterioscler Thromb Vasc Biol. 2012;32:2380-6 pubmed publisher
  44. Zhu L, Polley N, Mathews G, Delpire E. NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy Res. 2008;79:201-12 pubmed publisher
    ..Here we show that absence of NKCC1 in P9-P13 CA3 pyramidal neurons, through genetic manipulation or through bumetanide inhibition, results in a ..
  45. Diaz R, VAZQUEZ A, Dou H, Wei D, Cardell E, Lingrel J, et al. Conservation of hearing by simultaneous mutation of Na,K-ATPase and NKCC1. J Assoc Res Otolaryngol. 2007;8:422-34 pubmed potassium (K(+)) cycling within the inner ear, including K(+) channels, the Na-K-2Cl co-transporter (NKCC1), and the alpha(1) and alpha(2) isoforms of Na,K-ATPase...
  46. Han F, Tucker A, Lingrel J, Despa S, Bers D. Extracellular potassium dependence of the Na+-K+-ATPase in cardiac myocytes: isoform specificity and effect of phospholemman. Am J Physiol Cell Physiol. 2009;297:C699-705 pubmed publisher
  47. Bouyer P, Tang X, Weber C, Shen L, Turner J, Matthews J. Capsaicin induces NKCC1 internalization and inhibits chloride secretion in colonic epithelial cells independently of TRPV1. Am J Physiol Gastrointest Liver Physiol. 2013;304:G142-56 pubmed publisher
    ..capsaicin activated apical chloride conductance, had no effect on basolateral potassium conductance, but induced NKCC1 internalization demonstrated by immunocytochemistry and basolateral surface biotinylation...
  48. Antoine M, Vijayakumar S, McKeehan N, Jones S, Hebert J. The Severity of Vestibular Dysfunction in Deafness as a Determinant of Comorbid Hyperactivity or Anxiety. J Neurosci. 2017;37:5144-5154 pubmed publisher
    ..Furthermore, we show that (1) inner ear dysfunction due to the tissue-specific loss of Tbx1 or Slc12a2, which encodes a sodium-potassium-chloride cotransporter and is also necessary for inner ear function, causes ..
  49. Friedman L, Dror A, Mor E, Tenne T, Toren G, Satoh T, et al. MicroRNAs are essential for development and function of inner ear hair cells in vertebrates. Proc Natl Acad Sci U S A. 2009;106:7915-20 pubmed publisher
    ..Finally, we present indirect evidence that Slc12a2, Cldn12, and Bdnf mRNAs may be targets for miR-15a...
  50. Vanden Heuvel G, Payne J, Igarashi P, Forbush B. Expression of the basolateral Na-K-Cl cotransporter during mouse nephrogenesis and embryonic development. Gene Expr Patterns. 2006;6:1000-6 pubmed
    We examined the expression of Slc12a2 (NKCC1) transcripts in the developing mouse by Northern blot analysis and in situ hybridization (ISH) using riboprobes transcribed from a cDNA encoding the transmembrane domain of human Slc12a2...
  51. Su G, Kintner D, Flagella M, Shull G, Sun D. Astrocytes from Na(+)-K(+)-Cl(-) cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am J Physiol Cell Physiol. 2002;282:C1147-60 pubmed
    We reported previously that inhibition of Na(+)-K(+)-Cl(-) cotransporter isoform 1 (NKCC1) by bumetanide abolishes high extracellular K(+) concentration ([K(+)](o))-induced swelling and intracellular Cl(-) accumulation in rat cortical ..
  52. Kintner D, Luo J, Gerdts J, Ballard A, Shull G, Sun D. Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia. Am J Physiol Cell Physiol. 2007;292:C1113-22 pubmed
    Na(+)-K(+)-Cl(-) cotransporter isoform 1 (NKCC1) and reverse mode operation of the Na(+)/Ca(2+) exchanger (NCX) contribute to intracellular Na(+) and Ca(2+) overload in astrocytes following oxygen-glucose deprivation (OGD) and ..
  53. Ponce Coria J, Markadieu N, Austin T, Flammang L, Rios K, Welling P, et al. A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters. J Biol Chem. 2014;289:17680-8 pubmed publisher
    Na(+)-dependent chloride cotransporters (NKCC1, NKCC2, and NCC) are activated by phosphorylation to play critical roles in diverse physiological responses, including renal salt balance, hearing, epithelial fluid secretion, and volume ..
  54. Young Choi J, Ho Jung S, Namkung W, Lee J, Jin Son E, Wook Shin J, et al. Vestibular malformation in mice lacking Na-K-2Cl cotransporter 1 and expression of Na-K-2Cl cotransporter 1 in human vestibular end organs. Acta Otolaryngol. 2005;125:1252-7 pubmed
    ..NKCCl mRNA was expressed in both the human macula and crista ampullaris, and its protein was expressed mainly in the transitional and dark cell areas of the human crista ampullaris. ..
  55. Hunt D, Yamoah E, Krubitzer L. Multisensory plasticity in congenitally deaf mice: how are cortical areas functionally specified?. Neuroscience. 2006;139:1507-24 pubmed
  56. Sun L, Yu Z, Wang W, Liu X. Both NKCC1 and anion exchangers contribute to Cl? accumulation in postnatal forebrain neuronal progenitors. Eur J Neurosci. 2012;35:661-72 pubmed publisher
    ..However, the Na(+) -K(+) -2Cl(-) cotransporter displays an additional effect on neuronal progenitor proliferation. ..
  57. Hübner C, Stein V, Hermans Borgmeyer I, Meyer T, Ballanyi K, Jentsch T. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515-24 pubmed
    ..Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition. ..
  58. Kao L, Kurtz L, Shao X, Papadopoulos M, Liu L, Bok D, et al. Severe neurologic impairment in mice with targeted disruption of the electrogenic sodium bicarbonate cotransporter NBCe2 (Slc4a5 gene). J Biol Chem. 2011;286:32563-74 pubmed publisher
    ..Our findings are the first demonstration of the fundamental importance of NBCe2 in the biology of the nervous system. ..
  59. Garg P, Martin C, Elms S, Gordon F, Wall S, Garland C, et al. Effect of the Na-K-2Cl cotransporter NKCC1 on systemic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol. 2007;292:H2100-5 pubmed
    Studies in rat aorta have shown that the Na-K-2Cl cotransporter NKCC1 is activated by vasoconstrictors and inhibited by nitrovasodilators, contributes to smooth muscle tone in vitro, and is upregulated in hypertension...
  60. Walker N, Flagella M, Gawenis L, Shull G, Clarke L. An alternate pathway of cAMP-stimulated Cl secretion across the NKCC1-null murine duodenum. Gastroenterology. 2002;123:531-41 pubmed
    ..b>NKCC1, the epithelial Na(+)/K(+)/2Cl(-) cotransporter, is the major protein responsible for Cl(-) uptake...
  61. Mejia Gervacio S, Murray K, Lledo P. NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain. Neural Dev. 2011;6:4 pubmed publisher label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including ..
  62. Sid B, Miranda L, Vertommen D, Viollet B, Rider M. Stimulation of human and mouse erythrocyte Na(+)-K(+)-2Cl(-) cotransport by osmotic shrinkage does not involve AMP-activated protein kinase, but is associated with STE20/SPS1-related proline/alanine-rich kinase activation. J Physiol. 2010;588:2315-28 pubmed publisher
    This study was undertaken to investigate whether the mechanism of increased Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter activity by osmotic shrinkage involved AMP-activated protein kinase (AMPK) activation...
  63. Gagnon K, Delpire E. On the substrate recognition and negative regulation of SPAK, a kinase modulating Na+-K+-2Cl- cotransport activity. Am J Physiol Cell Physiol. 2010;299:C614-20 pubmed publisher
    ..proline-alanine-rich kinase (SPAK) for phosphorylation have been identified in Na+-K+-2Cl(-) cotransporter type 1 (NKCC1), NKCC2, and Na+-Cl(-) cotransporter (NCC)...
  64. Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, et al. Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II. Hypertension. 2013;62:872-8 pubmed publisher
    Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction...
  65. Jiang C, Kawabe H, Rotin D. The Ubiquitin Ligase Nedd4L Regulates the Na/K/2Cl Co-transporter NKCC1/SLC12A2 in the Colon. J Biol Chem. 2017;292:3137-3145 pubmed publisher depletion of basolateral Cl-, suggesting that Na+/K+/2Cl- (NKCC1/SLC12A2) co-transporter and ENaC are targets of Nedd4L in the colon...
  66. Ando Z, Sato S, Ikeda K, Kawakami K. Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. FEBS J. 2005;272:3026-41 pubmed
    ..assays indicated that the promoter region of one of the targets, sodium-potassium-chloride cotransporter 1 (Slc12a2), contains multiple Six1-binding sites and one common binding site of Six1 and Six4, suggesting that the DNA-..
  67. Dzhala V, Talos D, Sdrulla D, Brumback A, Mathews G, Benke T, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11:1205-13 pubmed
    ..The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons...
  68. Liu Y, Chu H, Chen J, Zhou L, Chen Q, Yu Y, et al. Age-related change in the expression of NKCC1 in the cochlear lateral wall of C57BL/6J mice. Acta Otolaryngol. 2014;134:1047-51 pubmed publisher
    Na(+)-K(+)-2Cl(-) co-transporter isoform 1 (NKCC1) mRNA and protein decrease with increasing age in the cochlear lateral wall of C57BL/6J (C57) mice...
  69. Miyoshi K, Shillingford J, Smith G, Grimm S, Wagner K, Oka T, et al. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol. 2001;155:531-42 pubmed
    ..Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, ..
  70. Frederikse P, Kasinathan C. KCC2 expression supersedes NKCC1 in mature fiber cells in mouse and rabbit lenses. Mol Vis. 2015;21:1142-50 pubmed
    Na-K-Cl cotransporter 1 (NKCC1) and K-Cl cotransporter 2 (KCC2) have fundamental roles in neuron differentiation that are integrated with gamma-aminobutyric acid (GABA) and glutamate receptors, GABA synthesized by GAD25/65/67 encoded by ..
  71. Nguyen M, Pace A, Koller B. Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia. J Exp Med. 2007;204:1383-93 pubmed
    The contribution of the Na(+)-K(+)-Cl(-) transporter (NKCC1) to fluid in ion transport and fluid secretion in the lung and in other secretory epithelia has been well established...
  72. Wang F, Wang X, Shapiro L, Cotrina M, Liu W, Wang E, et al. NKCC1 up-regulation contributes to early post-traumatic seizures and increased post-traumatic seizure susceptibility. Brain Struct Funct. 2017;222:1543-1556 pubmed publisher
    ..which is achieved by the opposing regulation of Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl--cotransporter 2 (KCC2)...
  73. O Keefe T, Williams G, Davies S, Neuberger M. Hyperresponsive B cells in CD22-deficient mice. Science. 1996;274:798-801 pubmed
    ..Thus, CD22 is a negative regulator of antigen receptor signaling whose onset of expression at the mature B cell stage may serve to raise the antigen concentration threshold required for B cell triggering. ..
  74. 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
    ..proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) with the cotransporters KCC3, NKCC1, and NKCC2 but not KCC1 and KCC4...
  75. Piechotta K, Garbarini N, England R, Delpire E. Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J Biol Chem. 2003;278:52848-56 pubmed
    Activity of heterologously expressed NKCC1 was analyzed under basal and activated conditions in the presence and absence of binding of Ste20-related proline-alanine-rich kinase (SPAK)...
  76. Ibla J, Khoury J, Kong T, Robinson A, Colgan S. Transcriptional repression of Na-K-2Cl cotransporter NKCC1 by hypoxia-inducible factor-1. Am J Physiol Cell Physiol. 2006;291:C282-9 pubmed
    ..of known ion transporters in Cl- -secreting epithelia revealed selective downregulation of Na-K-2Cl cotransporter NKCC1 mRNA, protein, and function...
  77. Li J, Chu H, Zhou L, Xiong H, Wang Y, Chen Q, et al. [Association of age-related hearing loss with ion transporter KCNQ1 and NKCC1 in cochlea of C57BL/6J mice]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2011;46:139-43 pubmed
    To investigate the age-related expression of KCNQ1 and NKCC1 ion transporters in the stria vascularis in the cochlea of C57BL/6J mice, and to analyze the relationship between the two ion transporters and age-related hearing loss...
  78. Luo J, Wang Y, Chen H, Kintner D, Cramer S, Gerdts J, et al. A concerted role of Na+ -K+ -Cl- cotransporter and Na+/Ca2+ exchanger in ischemic damage. J Cereb Blood Flow Metab. 2008;28:737-46 pubmed
    Na+-K+-Cl(-) cotransporter isoform 1 (NKCC1) and Na+/Ca2+ exchanger isoform 1 (NCX1) were expressed in cortical neurons...
  79. Batista Brito R, Machold R, Klein C, Fishell G. Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb Cortex. 2008;18:2306-17 pubmed publisher
    ..Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans. ..
  80. Geng Y, Hoke A, Delpire E. The Ste20 kinases Ste20-related proline-alanine-rich kinase and oxidative-stress response 1 regulate NKCC1 function in sensory neurons. J Biol Chem. 2009;284:14020-8 pubmed publisher
    b>NKCC1 is highly expressed in dorsal root ganglion neurons, where it is involved in gating sensory information...
  81. Wouters M, De Laet A, Donck L, Delpire E, Van Bogaert P, Timmermans J, et al. Subtractive hybridization unravels a role for the ion cotransporter NKCC1 in the murine intestinal pacemaker. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1219-27 pubmed
    ..for the tyrosine kinase receptor KIT, the established marker for ICC, and for the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1)...
  82. Chu H, Huang X, Xiong H, Han F, Wu Z, Zhou L, et al. [Role of ion channel Na-K-2Cl and alpha2 Na, K-ATPase in cochlear potassium cycling and auditory function]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2006;41:692-7 pubmed
    To investigate the auditory function and the role of NKCC1 and alpha2 Na, K-ATPase in the potassium recycling of cochlea. NKCC1(+/-) / alpha2 Na, K-ATPase(+/-) mice model was established from NKCC1(+/-) and alpha2 Na, K-ATPase(+/-) mice...
  83. Koltsova S, Kotelevtsev S, Tremblay J, Hamet P, Orlov S. Excitation-contraction coupling in resistance mesenteric arteries: evidence for NKCC1-mediated pathway. Biochem Biophys Res Commun. 2009;379:1080-3 pubmed publisher
    ..HCD outcome may be mediated by their interaction with NKCC1, the only isoform of Na(+), K(+), 2Cl(-) cotransporter expressed in VSMC as well as with targets distinct from ..
  84. Randall J, Thorne T, Delpire E. Partial cloning and characterization of Slc12a2: the gene encoding the secretory Na+-K+-2Cl- cotransporter. Am J Physiol. 1997;273:C1267-77 pubmed
    The Slc12a2 gene encodes a widely expressed bumetanide-sensitive Na+-K+-2Cl- cotransporter that participates in various functions such as Cl- secretion and cell volume regulation...