sodium potassium chloride symporters


Summary: A subclass of symporters that specifically transport SODIUM CHLORIDE and/or POTASSIUM CHLORIDE across cellular membranes in a tightly coupled process.

Top Publications

  1. Jang H, Kim S, Heo N, Lee J, Kim H, Nielsen S, et al. Effects of thiazide on the expression of TRPV5, calbindin-D28K, and sodium transporters in hypercalciuric rats. J Korean Med Sci. 2009;24 Suppl:S161-9 pubmed publisher
    ..The hypocalciuric effect of HCTZ is associated with increased protein abundance of TRPV5 in high salt or calcium diet-induced hypercalciuric rats. ..
  2. Gimenez I, Forbush B. Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2). Am J Physiol Renal Physiol. 2005;289:F1341-5 pubmed
    ..A chimeric NKCC containing the first 104 amino acids of NKCC1 on the NKCC2 backbone behaved essentially the same as NKCC2, further arguing against a major role for this upstream region in NKCC2 regulation. ..
  3. Nijenhuis T, Vallon V, Van Der Kemp A, Loffing J, Hoenderop J, Bindels R. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest. 2005;115:1651-8 pubmed
    ..Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation...
  4. Vinay L, Jean Xavier C. Plasticity of spinal cord locomotor networks and contribution of cation-chloride cotransporters. Brain Res Rev. 2008;57:103-10 pubmed
    ..This latter situation is observed early during development and in several pathological conditions, such as epilepsy, neuronal injury and chronic pain. ..
  5. Gavrikov K, Nilson J, Dmitriev A, Zucker C, Mangel S. Dendritic compartmentalization of chloride cotransporters underlies directional responses of starburst amacrine cells in retina. Proc Natl Acad Sci U S A. 2006;103:18793-8 pubmed
    ..The functional compartmentalization of interneuron dendrites may be an important means by which the nervous system encodes complex information at the subcellular level. ..
  6. Hattori T, Wang P. Involvement of Na(+)-K(+)-2Cl(-) cotransporters in hypertonicity-induced rise in intracellular calcium concentration. Int J Neurosci. 2006;116:1501-7 pubmed
    ..In conclusion, the findings obtained indicate that the Na+-K+-2Cl- cotransporters evoke cell depolarization and that this depolarization raises the [Ca(2+)]i by activating voltage-dependent Ca(2+) channels. ..
  7. Kiilerich P, Kristiansen K, Madsen S. Cortisol regulation of ion transporter mRNA in Atlantic salmon gill and the effect of salinity on the signaling pathway. J Endocrinol. 2007;194:417-27 pubmed
    ..In FW gills, GR1 and MR transcript levels were not significantly affected by cortisol. In SW gills, GR1 and MR transcripts were downregulated by cortisol; GR1 was regulated via the MR and MR regulation was mediated via GR. ..
  8. Zaarour N, Demaretz S, Defontaine N, Mordasini D, Laghmani K. A highly conserved motif at the COOH terminus dictates endoplasmic reticulum exit and cell surface expression of NKCC2. J Biol Chem. 2009;284:21752-64 pubmed publisher
    ..Taken together, these data are consistent with a model whereby naturally occurring premature terminations that interfere with the LLV motif compromise co-transporter surface delivery through defective trafficking. ..
  9. Brunet G, Gagnon E, Simard C, Daigle N, Caron L, Noël M, et al. Novel insights regarding the operational characteristics and teleological purpose of the renal Na+-K+-Cl2 cotransporter (NKCC2s) splice variants. J Gen Physiol. 2005;126:325-37 pubmed

More Information


  1. Ortiz P. cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP. Am J Physiol Renal Physiol. 2006;290:F608-16 pubmed
    ..min(-1).mm(-1); not significant). We concluded that cAMP increases NKCC2 surface expression by a mechanism involving VAMP and that NKCC2 trafficking to the apical membrane is involved in the stimulation of TAL NaCl absorption by cAMP. ..
  2. Hamann S, Herrera Pérez J, Bundgaard M, Alvarez Leefmans F, Zeuthen T. Water permeability of Na+-K+-2Cl- cotransporters in mammalian epithelial cells. J Physiol. 2005;568:123-35 pubmed
    ..This suggests that the cotransporters of the two tissues are either different isoforms or the same cotransporter but in two different transport modes. ..
  3. Galan A, Cervero F. Painful stimuli induce in vivo phosphorylation and membrane mobilization of mouse spinal cord NKCC1 co-transporter. Neuroscience. 2005;133:245-52 pubmed
  4. Vitari A, Thastrup J, Rafiqi F, Deak M, Morrice N, Karlsson H, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223-31 pubmed
    ..These data establish that the CCT domain functions as a multipurpose docking site, enabling SPAK/OSR1 to interact with substrates (NKCC1) and activators (WNK1/WNK4). ..
  5. Valencia de Ita S, Lawand N, Lin Q, Castaneda Hernandez G, Willis W. Role of the Na+-K+-2Cl- cotransporter in the development of capsaicin-induced neurogenic inflammation. J Neurophysiol. 2006;95:3553-61 pubmed
    ..Taken together these results suggest that NKCC is involved in the increases in DRR activity, neurogenic inflammation and hyperalgesia and allodynia induced by intradermal CAP. ..
  6. Flatman P. Cotransporters, WNKs and hypertension: important leads from the study of monogenetic disorders of blood pressure regulation. Clin Sci (Lond). 2007;112:203-16 pubmed
    ..This new knowledge should not only help us target antihypertensive therapy more appropriately, but could also provide the basis for developing new therapeutic approaches to essential hypertension. ..
  7. Pieraut S, Laurent Matha V, Sar C, Hubert T, Mechaly I, Hilaire C, et al. NKCC1 phosphorylation stimulates neurite growth of injured adult sensory neurons. J Neurosci. 2007;27:6751-9 pubmed
    ..Our results clearly show that NKCC1-induced increase in intracellular chloride concentration is a major event accompanying peripheral nerve regeneration. ..
  8. Pitcher M, Price T, Entrena J, Cervero F. Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia. Mol Pain. 2007;3:17 pubmed
    ..Moreover, they suggest that endogenous TRPV1 agonists, released in the CNS in painful conditions, might stimulate TRPV1 receptors on primary afferents that, in turn, play a role in increasing NKCC1 activity leading to allodynia. ..
  9. 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
    ..In summary, our study demonstrates redundancy of kinases in the regulation of NKCC1 in dorsal root ganglion neurons. ..
  10. Benziane B, Demaretz S, Defontaine N, Zaarour N, Cheval L, Bourgeois S, et al. NKCC2 surface expression in mammalian cells: down-regulation by novel interaction with aldolase B. J Biol Chem. 2007;282:33817-30 pubmed
  11. Dmitriev A, Dmitrieva N, Keyser K, Mangel S. Multiple functions of cation-chloride cotransporters in the fish retina. Vis Neurosci. 2007;24:635-45 pubmed
    ..In addition, the anatomical and electrophysiological results together suggest that all of the major neuronal types in the fish retina are influenced by chloride cotransporter activity. ..
  12. Parvin M, Gerelsaikhan T, Turner R. Regions in the cytosolic C-terminus of the secretory Na(+)-K(+)-2Cl(-) cotransporter NKCC1 are required for its homodimerization. Biochemistry. 2007;46:9630-7 pubmed
    ..These latter results indicate that there is a functional interaction between dimer subunits but that nonfunctional subunits do not necessarily have a dominant negative effect as has been previously proposed. ..
  13. Ares G, Caceres P, Alvarez Leefmans F, Ortiz P. cGMP decreases surface NKCC2 levels in the thick ascending limb: role of phosphodiesterase 2 (PDE2). Am J Physiol Renal Physiol. 2008;295:F877-87 pubmed publisher
    ..We conclude that cGMP decreases NKCC2 levels in the apical membrane of THALs and that this effect is mediated by PDE2. This is an important mechanism by which cGMP inhibits NaCl absorption by the THAL. ..
  14. Gagnon E, Bergeron M, Daigle N, Lefoll M, Isenring P. Molecular mechanisms of cation transport by the renal Na+-K+-Cl- cotransporter: structural insight into the operating characteristics of the ion transport sites. J Biol Chem. 2005;280:32555-63 pubmed
    ..Because such residues should be adjacent to one another on the vertical axis of the tm2 alpha-helix, our results imply, furthermore, that the ion transport sites in NKCC2 could be physically linked...
  15. 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
    ..Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures. ..
  16. Ponce Coria J, San Cristobal P, Kahle K, Vazquez N, Pacheco Alvarez D, de los Heros P, et al. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proc Natl Acad Sci U S A. 2008;105:8458-63 pubmed publisher
  17. Matskevich I, Hegney K, Flatman P. Regulation of erythrocyte Na-K-2Cl cotransport by threonine phosphorylation. Biochim Biophys Acta. 2005;1714:25-34 pubmed
    ..Experiments on cotransporter precipitation with microcystin sepharose suggest that PrP-1 binds to a phosphorylated form of the cotransporter. ..
  18. Castrop H, Schnermann J. Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Renal Physiol. 2008;295:F859-66 pubmed publisher
  19. Lauf P, Chimote A, Adragna N. Lithium fluxes indicate presence of Na-Cl cotransport (NCC) in human lens epithelial cells. Cell Physiol Biochem. 2008;21:335-46 pubmed publisher
    ..However, a K-independent and moderately thiazide-sensitive ClD-Li flux, i.e. LiCC, likely occurring through NCC was detected operationally and molecularly...
  20. Paredes A, Plata C, Rivera M, Moreno E, Vazquez N, Muñoz Clares R, et al. Activity of the renal Na+-K+-2Cl- cotransporter is reduced by mutagenesis of N-glycosylation sites: role for protein surface charge in Cl- transport. Am J Physiol Renal Physiol. 2006;290:F1094-102 pubmed
    ..Our data demonstrate that NKCC2 is glycosylated and suggest that prevention of glycosylation reduces its functional expression by affecting insertion into the plasma membrane and the intrinsic activity of the cotransporter. ..
  21. 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
  22. Price T, Hargreaves K, Cervero F. Protein expression and mRNA cellular distribution of the NKCC1 cotransporter in the dorsal root and trigeminal ganglia of the rat. Brain Res. 2006;1112:146-58 pubmed
    ..Moreover, these results suggest the possibility of a functional role of NKCC1 in the glial cells closely apposed to primary sensory afferents. ..
  23. Nomura H, Sakai A, Nagano M, Umino M, Suzuki H. Expression changes of cation chloride cotransporters in the rat spinal cord following intraplantar formalin. Neurosci Res. 2006;56:435-40 pubmed
    ..These results suggest that KCC2, rather than NKCC1, mainly contributes to modulating excitability of the dorsal spinal cord neurons in the initial stage of formalin-evoked hyperalgesia. ..
  24. Shiozaki A, Miyazaki H, Niisato N, Nakahari T, Iwasaki Y, Itoi H, et al. Furosemide, a blocker of Na+/K+/2Cl- cotransporter, diminishes proliferation of poorly differentiated human gastric cancer cells by affecting G0/G1 state. J Physiol Sci. 2006;56:401-6 pubmed
  25. Gimenez I, Forbush B. The residues determining differences in ion affinities among the alternative splice variants F, A, and B of the mammalian renal Na-K-Cl cotransporter (NKCC2). J Biol Chem. 2007;282:6540-7 pubmed
  26. Flatman P. Cotransporters, WNKs and hypertension: an update. Curr Opin Nephrol Hypertens. 2008;17:186-92 pubmed publisher
    ..Hypertension-associated mutant WNKs increase surface expression and activation of renal tubular NKCC2 and NCC. Whether this adequately explains the hypertension awaits studies of these mutants in other tissues. ..
  27. Oppermann M, Mizel D, Huang G, Li C, Deng C, Theilig F, et al. Macula densa control of renin secretion and preglomerular resistance in mice with selective deletion of the B isoform of the Na,K,2Cl co-transporter. J Am Soc Nephrol. 2006;17:2143-52 pubmed
    ..Nevertheless, the high-affinity NKCC2B contributes to salt absorption and macula densa function in the low NaCl concentration range. ..
  28. Price T, Cervero F, De Koninck Y. Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Curr Top Med Chem. 2005;5:547-55 pubmed
    ..Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics. ..
  29. Hebert S, Mount D, Gamba G. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch. 2004;447:580-93 pubmed
    ..In addition, knockout mice for many members of this family have generated important new information regarding their respective physiological roles. ..
  30. Gagnon E, Forbush B, Caron L, Isenring P. Functional comparison of renal Na-K-Cl cotransporters between distant species. Am J Physiol Cell Physiol. 2003;284:C365-70 pubmed
    ..We have also found that the renal NKCC2 of distant vertebrates share similar affinities for cations. This finding points to the existence of highly conserved residues that mediate the kinetic behavior of the NKCC2 splice variants. ..
  31. Simard C, Brunet G, Daigle N, Montminy V, Caron L, Isenring P. Self-interacting domains in the C terminus of a cation-Cl- cotransporter described for the first time. J Biol Chem. 2004;279:40769-77 pubmed
    ..A model is proposed in which the carrier could alternate between monomeric and homo-oligomeric units via chemical- or ligand-dependent changes in conformational dynamics. ..
  32. Yamada J, Okabe A, Toyoda H, Kilb W, Luhmann H, Fukuda A. Cl- uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J Physiol. 2004;557:829-41 pubmed
    ..These data suggest that NKCC1 may play a pivotal role in the generation of GABA-mediated depolarization in immature CP cells, while KCC2 promotes the later maturation of GABAergic inhibition in the rat neocortex. ..
  33. Dowd B, Forbush B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1). J Biol Chem. 2003;278:27347-53 pubmed
    ..In cells preloaded with 32Pi, the phosphorylation of PASK, but not DNPASK, coincides with that of NKCC1 and increases 5.5 +/- 0.36-fold in low [Cl]e. These data conclusively link PASK with the phosphorylation and activation of NKCC1...
  34. Starremans P, Kersten F, Knoers N, van den Heuvel L, Bindels R. Mutations in the human Na-K-2Cl cotransporter (NKCC2) identified in Bartter syndrome type I consistently result in nonfunctional transporters. J Am Soc Nephrol. 2003;14:1419-26 pubmed
    ..These results are in line with the hypothesis that the mutations in hNKCC2 are the underlying cause of the clinical abnormalities seen in patients with type I BS...
  35. Song J, Knepper M, Verbalis J, Ecelbarger C. Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes. Am J Physiol Renal Physiol. 2003;285:F1125-37 pubmed
    ..These comprehensive changes would be expected to decrease volume contraction accompanying large-solute and water losses associated with DM. ..
  36. Gagnon E, Forbush B, Flemmer A, Gimenez I, Caron L, Isenring P. Functional and molecular characterization of the shark renal Na-K-Cl cotransporter: novel aspects. Am J Physiol Renal Physiol. 2002;283:F1046-55 pubmed
  37. Kim D, Sands J, Klein J. Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats. Am J Physiol Renal Physiol. 2003;285:F303-9 pubmed
    ..UT-B and ROMK were unchanged at any time point. The increases in UT-A1, AQP2, and NKCC2/BSC1 proteins during uncontrolled DM would tend to limit the loss of fluid and solute during uncontrolled diabetes. ..
  38. Maglova L, Crowe W, Russell J. Perinuclear localization of Na-K-Cl-cotransporter protein after human cytomegalovirus infection. Am J Physiol Cell Physiol. 2004;286:C1324-34 pubmed
  39. Laird J, Garcia Nicas E, Delpire E, Cervero F. Presynaptic inhibition and spinal pain processing in mice: a possible role of the NKCC1 cation-chloride co-transporter in hyperalgesia. Neurosci Lett. 2004;361:200-3 pubmed
  40. Iwamoto L, Fujiwara N, Nakamura K, Wada R. Na-K-2Cl cotransporter inhibition impairs human lung cellular proliferation. Am J Physiol Lung Cell Mol Physiol. 2004;287:L510-4 pubmed
    ..Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation. ..
  41. Na K, Oh Y, Han J, Joo K, Lee J, Earm J, et al. Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats. Am J Physiol Renal Physiol. 2003;284:F133-43 pubmed
    ..These increases in the abundance of Na(+) transporters in response to chronic diuretic treatment may account for the generation of diuretic tolerance associated with long-term diuretic use. ..
  42. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85:423-93 pubmed
  43. 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
    ..In phasic portal vein smooth muscle from Nkcc1(-/-) mice, however, a sharp reduction in mechanical force was noted. These results indicate that NKCC1 can be important for the maintenance of normal blood pressure and vascular tone. ..
  44. Gosmanov A, Lindinger M, Thomason D. Riding the tides: K+ concentration and volume regulation by muscle Na+-K+-2Cl- cotransport activity. News Physiol Sci. 2003;18:196-200 pubmed
  45. Alvarez L, Candia O, Polikoff L. Beta-adrenergic stimulation of Na(+)-K(+)-2Cl(-) cotransport activity in the rabbit lens. Exp Eye Res. 2003;76:61-70 pubmed
    ..As such, this study provides the first indication for the regulation of lens transport by adrenoceptors, presumably of the beta-2 subtype. ..
  46. Iwamoto L, Nakamura K, Wada R. Immunolocalization of a Na-K-2Cl cotransporter in human tracheobronchial smooth muscle. J Appl Physiol (1985). 2003;94:1596-601 pubmed
    ..Our present findings thus document the presence of a functional NKCC cotransporter in human airway smooth muscle, providing a basis for defining the role of this ion cotransporter in airway smooth muscle function. ..
  47. Gimenez I, Forbush B. Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein. J Biol Chem. 2003;278:26946-51 pubmed
  48. 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
    ..We conclude that several cation chloride co-transporters interact with SPAK and/or OSR1, and we hypothesize that this interaction might play a role during the initiation of the cellular stress response. ..
  49. Ikeda M, Toyoda H, Yamada J, Okabe A, Sato K, Hotta Y, et al. Differential development of cation-chloride cotransporters and Cl- homeostasis contributes to differential GABAergic actions between developing rat visual cortex and dorsal lateral geniculate nucleus. Brain Res. 2003;984:149-59 pubmed
    ..Such differential GABAergic actions may underlie the distinct mechanisms involved in VC and dLGN development within the visual system. ..
  50. Starremans P, Kersten F, van den Heuvel L, Knoers N, Bindels R. Dimeric architecture of the human bumetanide-sensitive Na-K-Cl Co-transporter. J Am Soc Nephrol. 2003;14:3039-46 pubmed
    ..In conclusion, this study suggests that hNKCC2 forms at least functional dimers when expressed in Xenopus laevis oocytes of which the individual subunits transport Na(+) independently. ..
  51. Ferenczi E, Fraser J, Chawla S, Skepper J, Schwiening C, Huang C. Membrane potential stabilization in amphibian skeletal muscle fibres in hypertonic solutions. J Physiol. 2004;555:423-38 pubmed
    ..In situations where P(Cl)/P(K) is low, the same co-transporters would instead permit RVIs but at the expense of a capacity to stabilize E(m). ..
  52. Simard C, Daigle N, Bergeron M, Brunet G, Caron L, Noël M, et al. Characterization of a novel interaction between the secretory Na+-K+-Cl- cotransporter and the chaperone hsp90. J Biol Chem. 2004;279:48449-56 pubmed
    ..Further studies will be required to elucidate the functional relevance of this novel interaction...
  53. O Donnell M, Tran L, Lam T, Liu X, Anderson S. Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab. 2004;24:1046-56 pubmed
    ..Bumetanide also reduced infarct size, determined by TTC staining. These findings suggest that a luminal BBB Na-K-Cl cotransporter contributes to edema formation during cerebral ischemia. ..
  54. Fernandez Llama P, Ageloff S, Fernandez Varo G, Ros J, Wang X, Garra N, et al. Sodium retention in cirrhotic rats is associated with increased renal abundance of sodium transporter proteins. Kidney Int. 2005;67:622-30 pubmed
  55. Granados Soto V, Arguelles C, Alvarez Leefmans F. Peripheral and central antinociceptive action of Na+-K+-2Cl- cotransporter blockers on formalin-induced nociception in rats. Pain. 2005;114:231-8 pubmed
    ..Our data suggest that the Na(+)-K(+)-2Cl(-) cotransporter localized in sensory neurons at intraspinal and peripheral sites is involved in formalin-induced nociception. ..
  56. Barmashenko G, Schmidt M, Hoffmann K. Differences between cation-chloride co-transporter functions in the visual cortex of pigmented and albino rats. Eur J Neurosci. 2005;21:1189-95 pubmed
    ..These results are discussed in relation to functional alterations in the albino visual system. ..