Genomes and Genes
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.
- 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. ..
- 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. ..
- 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
- 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). ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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
- 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. ..
- 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. ..
- 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. ..
- 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...
- 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. ..
- 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. ..
- 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...
- 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. ..
- 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. ..
- 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. ..
- 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
- 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
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- 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...
- 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...
- 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. ..
- 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
- 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. ..
- 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
- 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
- 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. ..
- 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. ..
- Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85:423-93 pubmed
- 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. ..
- 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
- 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. ..
- 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. ..
- 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
- 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. ..
- 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. ..
- 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. ..
- 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). ..
- 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...
- 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. ..
- 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
- 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. ..
- 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. ..