Abstract
The electroneutral Na+–K+–Cl− cotransporters NKCC1 (encoded by the SLC12A2 gene) and NKCC2 (SLC12A1 gene) belong to the Na+-dependent subgroup of solute carrier 12 (SLC12) family of transporters. They mediate the electroneutral movement of Na+ and K+, tightly coupled to the movement of Cl− across cell membranes. As they use the energy of the ion gradients generated by the Na+/K+-ATPase to transport Na+, K+, and Cl− from the outside to the inside of a cell, they are considered secondary active transport mechanisms. NKCC-mediated transport occurs in a 1Na+, 1K+, and 2Cl− ratio, although NKCC1 has been shown to sometimes mediate partial reactions. Both transporters are blocked by bumetanide and furosemide, drugs which are commonly used in clinical medicine. NKCC2 is the molecular target of loop diuretics as it is expressed on the apical membrane of thick ascending limb of Henle epithelial cells, where it mediates NaCl reabsorption. NKCC1, in contrast, is found on the basolateral membrane of Cl− secretory epithelial cells, as well as in a variety of non-epithelial cells, where it mediates cell volume regulation and participates in Cl− homeostasis. Following their molecular identification two decades ago, much has been learned about their biophysical properties, their mode of operation, their regulation by kinases and phosphatases, and their physiological relevance. However, despite this tremendous amount of new information, there are still so many gaps in our knowledge. This review summarizes information that constitutes consensus in the field, but it also discusses current points of controversy and highlights many unanswered questions.
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References
Altamirano AA, Breitwieser GE, Russel JM (1988) Vanadate and fluoride effects on Na–K–Cl cotransport in squid giant axon. Am J Physiol 254:C582–C586
Alvarez-Leefmans FJ, Gamiño SM, Giraldez F et al (1988) Intracellular chloride regulation in amphibian dorsal root ganglion neurons studied with ion-selective microelectrodes. J Physiol Lond 406:225–246
Ares GR, Caceres P, Alvarez-Leefmans FJ et al (2008) cGMP decreases surface NKCC2 levels in the thick ascending limb: role of phosphodiesterase 2 (PDE2). Am J Physiol Renal Physiol 295:F877–F887
Ares GR, Caceres PS, Ortiz PA (2011) Molecular regulation of NKCC2 in the thick ascending limb. Am J Physiol Renal Physiol 301:F1143–F1159
Balakrishnan V, Becker M, Lohrke S et al (2003) Expression and function of chloride transporters during development of inhibitory neurotransmission in the auditory brainstem. J Neurosci 23:4134–4145
Bennett CM, Brenner BM, Berliner RW (1968) Micropuncture study of nephron function in the rhesus monkey. J Clin Invest 47:203–216
Bergeron MJ, Gagnon E, Wallendorff B et al (2003) Ammonium transport and pH regulation by K(+)–Cl(−) cotransporters. Am J Physiol Renal Physiol 285:F68–F78
Boudeau J, Baas AF, Deak M et al (2003) MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. Embo J 22:5102–5114
Brumback AC, Staley KJ (2008) Thermodynamic regulation of NKCC1-mediated Cl− cotransport underlies plasticity of GABA(A) signaling in neonatal neurons. J Neurosci 28:1301–1312
Caceres PS, Ares GR, Ortiz PA (2009) cAMP stimulates apical exocytosis of the renal Na(+)–K(+)–2Cl(−) cotransporter NKCC2 in the thick ascending limb: role of protein kinase A. J Biol Chem 284:24965–24971
Calò LA (2006) Vascular tone control in humans: insights from studies in Bartter’s/Gitelman’s syndromes. Kidney Int 69:963–966
Capasso G, Rizzo M, Evangelista C et al (2005) Altered expression of renal apical plasma membrane Na + transporters in the early phase of genetic hypertension. Am J Physiol Renal Physiol 288:F1173–F1182
Carmosino M, Giménez I, Caplan M et al (2008) Exon loss accounts for differential sorting of Na–K–Cl cotransporters in polarized epithelial cells. Mol Biol Cell 19:4341–4351
Carmosino M, Procino G, Svelto M (2012) Na + −K + −2Cl − cotransporter type 2 trafficking and activity: the role of interacting proteins. Biol Cell 104:201–212
Carmosino M, Rizzo F, Ferrari P et al (2011) NKCC2 is activated in Milan hypertensive rats contributing to the maintenance of salt-sensitive hypertension. Pflügers Arch Eur J Physiol 462:281–291
Carmosino M, Rizzo F, Procino G et al (2010) MAL/VIP17, a new player in the regulation of NKCC2 in the kidney. Mol Biol Cell 21:3985–3997
Carmosino M, Rizzo F, Torretta S et al (2013) High-throughput fluorescent-based NKCC functional assay in adherent epithelial cells. BMC Cell Biol 14:16
Carota I, Theilig F, Oppermann M et al (2010) Localization and functional characterization of the human NKCC2 isoforms. Acta Physiol (Oxf) 199:327–338
Castrop H, Schnermann J (2008) Isoforms of renal Na–K–2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Renal Physiol 295:F859–F866
Cho HM, Lee HA, Kim HY et al (2011) Expression of Na+–K+–2Cl− cotransporter 1 is epigenetically regulated during postnatal development of hypertension. Am J Hypertens 24:1286–1293
Cui CY, Childress V, Piao Y et al (2012) Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na–K–Cl cotransporter 1. Proc Natl Acad Sci U S A 109:1199–1203
Darman RB, Flemmer A, Forbush BI (2001) Modulation of ion transport by direct targeting of PP1 to the Na–K–Cl cotransporter. J Biol Chem 276:34359–34362
Darman RB, Forbush B (2002) A regulatory locus of phosphorylation in the N terminus of the Na–K–Cl cotransporter, NKCC1. J Biol Chem 277:37542–37550
DeFazio RA, Heger S, Ojeda SR et al (2002) Activation of A-type gamma-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons. Mol Endocrinol 16:2872–2891
Delpire E, Days E, Mi D et al (2009) Small molecule screen identifies inhibitors of the neuronal K–Cl cotransporter KCC2. Proc Natl Acad Sci U S A 106:5383–5388
Delpire E, Gagnon KB (2011) Kinetics of hyperosmotically-stimulated Na–K–2Cl cotransporter in Xenopus laevis oocytes. Am J Physiol Cell Physiol 301:C1074–C1085
Delpire E, Lu J, England R et al (1999) Deafness and imbalance associated with inactivation of the secretory Na–K–2Cl co-transporter. Nat Genet 22:192–195
Delpire E, Rauchman MI, Beier DR et al (1994) 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 269:25677–25683
Dietz KJ, Vogel MO, Viehhauser A (2010) AP2/EREBP transcription factors are part of gene regulatory networks and integrate metabolic, hormonal and environmental signals in stress acclimation and retrograde signalling. Protoplasma 245:3–14
Dixon MJ, Gazzard J, Chaudhry SS et al (1999) Mutation of the Na–K–Cl co-transporter gene Slc12a2 results in deafness in mice. Hum Mol Genet 8:1579–1584
Dowd BF, Forbush B (2003) PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na–K–Cl cotransporter (NKCC1). J Biol Chem 278:27347–27353
Dzhala VI, Talos DM, Sdrulla DA et al (2005) NKCC1 transporter facilitates seizures in the developing brain. Nat Med 11:1205–1213
Eftekhari S, Mehvari Habibabadi J, Najafi Ziarani M et al (2013) Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia 54:e9–e12
Evans RL, Park K, Turner RJ et al (2000) Severe impairment of salivation in Na+/K+/2Cl− cotransporter (NKCC1)-deficient mice. J Biol Chem 275:26720–26726
Feldstein AE, Miller SM, El-Youssef M et al (2003) Chronic intestinal pseudoobstruction associated with altered interstitial cells of Cajal networks. J Pediatr Gastroenterol Nutr 36:492–497
Filippi BM, de los Heros P, Mehellou Y et al (2011) MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. Embo J 30:1730–1741
Flagella M, Clarke LL, Miller ML et al (1999) Mice lacking the basolateral Na–K–2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem 274:26946–26955
Flemmer AW, Gimenez I, Dowd BF et al (2002) Activation of the Na–K–Cl cotransporter NKCC1 detected with a phospho-specific antibody. J Biol Chem 277:37551–37558
Fraser SA, Gimenez I, Cook N et al (2007) Regulation of the renal-specific Na+–K+–2Cl− co-transporter NKCC2 by AMP-activated protein kinase (AMPK). Biochem J 405:85–93
Gagnon KB, Delpire E (2010) Molecular determinants of hyperosmotically activated NKCC1-mediated K+/K+ exchange. J Physiol Lond 588:3385–3396
Gagnon KB, Delpire E (2010) Multiple pathways for protein phosphatase 1 (PP1) regulation of Na–K–2Cl cotransporter (NKCC1) function. The N-terminal tail of the Na–K–2Cl cotransporter serves as a regulatory scaffold for Ste20-related proline/alanine-rich kinase (SPAK) and PP1. J Biol Chem 285:14115–14121
Gagnon KB, Delpire E (2012) Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiol Rev 92:1577–1617
Gagnon KB, Delpire E (2013) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically-engineered mouse knockouts. Am J Physiol Cell Physiol 304:C693–C714
Gagnon KB, England R, Delpire E (2006) Volume sensitivity of cation–chloride cotransporters is modulated by the interaction of two kinases: SPAK and WNK4. Am J Physiol Cell Physiol 290:C134–C142
Gagnon KB, England R, Delpire E (2007) A single binding motif is required for SPAK activation of the Na–K–2Cl cotransporter. Cell Physiol Biochem 20:131–142
Gagnon KB, England R, Diehl L et al (2007) Apoptosis associated tyrosine kinase scaffolding of protein phosphatase 1 and SPAK reveals a novel pathway for Na–K–2C1 cotransporter regulation. Am J Physiol Cell Physiol 292:C1809–C1815
Gamba G, Miyanoshita A, Lombardi M et al (1994) Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium–(potassium)–chloride cotransporter family expressed in kidney. J Biol Chem 269:17713–17722
Garg P, Martin CF, Elms SC et al (2007) Effect of the Na–K–2Cl cotransporter NKCC1 on systemic blood pressure and smooth muscle tone. Am J Physiol Heart Circ Physiol 292:H2100–H2105
Geck P, Heinz E (1986) The Na–K–2Cl cotransport system. J Membrane Biol 91:97–105
Geck P, Pietrzyk C, Burckhardt B-C et al (1980) Electrically silent cotransport of Na+, K+ and Cl− in Ehrlich cells. Biochim Biophys Acta 600:432–447
Geng Y, Hoke A, Delpire E (2009) The Ste20 kinases SPAK and OSR1 regulate NKCC1 function in sensory neurons. J Biol Chem 284:14020–14028
Gerelsaikhan T, Turner RJ (2000) Transmembrane topology of the secretory Na+–K+–2Cl− cotransporter NKCC1 studied by in vitro translation. J Biol Chem 275:40471–40477
Giménez I (2006) Molecular mechanisms and regulation of furosemide-sensitive Na–K–Cl cotransporters. Curr Opin Nephrol Hypertens 15:517–523
Giménez I, Forbush B (2003) Short-term stimulation of the renal Na–K–Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein. J Biol Chem 278:26946–26951
Gimenez I, Forbush B (2005) Regulatory phosphorylation sites in the NH2 terminus of the renal Na–K–Cl cotransporter (NKCC2). Am J Physiol Renal Physiol 289:F1341–F1345
Greger R, Schlatter E (1981) Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Pfluegers Arch 392:92–94
Grimm PR, Liu J, Coleman R et al (2011) Phosphorylation-dependent regulation of NCC is blunted in SPAK null mice (SPAK−/−). FASEB J 25:1041.26
Grubb BR, Pace AJ, Lee E et al (2001) Alterations in airway ion transport in NKCC1-deficient mice. Am J Physiol Cell Physiol 281:C615–C623
Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell volume regulation in vertebrates. Physiol Rev 89:193–277
Ibla JC, Khoury J, Kong T et al (2006) Transcriptional repression of Na–K–2Cl cotransporter NKCC1 by hypoxia-inducible factor-1. Am J Physiol Cell Physiol 291:C282–C289
Igarashi P, Vanden Heuvel GB, Payne JA et al (1995) Cloning, embryonic expression and alternative splicing of a murine kidney specific Na–K–Cl cotransporter. Am J Physiol (Renal Fluid Electrolyte Physiol) 269:F405–F418
Igarashi P, Vanden Heuvel GB, Quaggin SE et al (1994) Cloning, embryonic expression, and chromosomal localization of murine renal Na–K–Cl cotransporter (NKCC2). J Am Soc Nephrol 5:288
Igarashi P, Whyte DA, Li K et al (1996) Cloning and kidney cell-specific activity of the promoter of the murine renal Na–K–Cl cotransporter gene. J Biol Chem 271:9666–9674
Ikebe M, Nonoguchi H, Nakayama Y et al (2001) Upregulation of the secretory-type Na(+)/K(+)/2Cl(−)-cotransporter in the kidney by metabolic acidosis and dehydration in rats. J Am Soc Nephrol 12:423–430
Isenring P, Jacoby SC, Chang J et al (1998) Mutagenic mapping of the Na–K–Cl cotransporter for domains involved in ion transport and bumetanide binding. J Gen Physiol 112:549–558
Isenring P, Jacoby SC, Forbush BI (1998) The role of transmembrane domain 2 in cation transport by the Na–K–Cl cotransporter. Proc Natl Acad Sci U S A 95:7179–7184
Jakab RL, Collaco AM, Ameen NA (2011) Physiological relevance of cell-specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt–villus axis in the intestine. Am J Physiol Gastrointest Liver Physiol 300:G82–G98
Kaplan MR, Mount DB, Delpire E et al (1996) Molecular mechanisms of NaCl cotransport. Annu Rev Physiol 58:649–668
Kaplan MR, Plotkin MD, Brown D et al (1996) Expression of the mouse Na–K–2Cl cotransporter, mBSC2, in the terminal IMCD, the glomerular and extraglomerular mesangium and the glomerular afferent arteriole. J Clin Invest 98:723–730
Kaplan MR, Plotkin MD, Lee W-S et al (1996) Apical localization of the Na–K–2Cl cotransporter, rBSC1, on rat thick ascending limbs. Kidney Int 49:40–47
Karim Z, Attmane-Elakeb A, Sibella V et al (2003) Acid pH increases the stability of BSC1/NKCC2 mRNA in the medullary thick ascending limb. J Am Soc Nephrol 14:2229–2214
Kelley LA, Sternberg MJE (2009) Protein structure prediction on the web: a case study using the Phyre server. Nat Protoc 4:363–371
Kim HY (2009) Renal handling of ammonium and acid base regulation. Electrolyte Blood Press 7:9–13
Krug AW, Papavassiliou F, Hopfer U et al (2003) Aldosterone stimulates surface expression of NHE3 in renal proximal brush borders. Pfluegers Arch 446:492–496
Lee MP, Ravenel JD, Hu RJ et al (2000) Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest 106:1447–1455
Li Y, Hu J, Vita R et al (2004) SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. Embo J 23:1112–1122
Lin SH, Yu IS, Jiang ST et al (2011) 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 108:17538–17543
Loffing J, Schild L (2005) Functional domains of the epithelial sodium channel. J Am Soc Nephrol 16:3175–3181
Lytle C, Forbush BI (1992) The Na–K–Cl cotransport protein of shark rectal gland. II. Regulation by direct phosphorylation. J Biol Chem 267:25438–25443
Lytle C, Forbush BI (1996) Regulatory phosphorylation of the secretory Na–K–Cl cotransporter: modulation by cytoplasmic Cl. Am J Physiol Cell Physiol 270:C437–C448
Lytle C, McManus TJ, Haas M (1998) A model of Na–K–2Cl cotransport based on ordered ion binding and glide symmetry. Am J Physiol 274:C299–C309
Malnic G, Klose RM, Giebisch G (1966) Micropuncture study of distal tubular potassium and sodium transport in rat nephron. Am J Physiol 211:529–547
McCormick JA, Ellison DH (2011) The WNKs: atypical protein kinases with pleiotropic actions. Physiol Rev 91:177–219
McCormick JA, Mutig K, Nelson JH et al (2011) A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metab 14:352–364
McManus TJ (1987) Na, K,2Cl cotransport: kinetics and mechanism. Fed Proc 46:2377–2394
Monette MY, Forbush B (2012) Regulatory activation is accompanied by movement in the C terminus of the Na–K–Cl cotransporter (NKCC1). J Biol Chem 287:2210–2220
Moore-Hoon ML, Turner RJ (2000) The structural unit of the secretory Na+–K+–2Cl− cotransporter (NKCC1) is a homodimer. Biochemistry 39:3718–3724
Mutig K, Paliege A, Kahl T et al (2007) Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL. Am J Physiol Renal Physiol 293:F1166–F1177
Neyroud N, Tesson F, Denjoy I et al (1997) A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Gen 15:186–189
Nezu A, Parvin MN, Turner RJ (2009) A conserved hydrophobic tetrad near the C terminus of the secretory Na+–K+–2Cl− cotransporter (NKCC1) is required for its correct intracellular processing. J Biol Chem 284:6869–6876
O’Mahony F, Toumi F, Mroz MS et al (2008) Induction of Na+/K+/2Cl− cotransporter expression mediates chronic potentiation of intestinal epithelial Cl − secretion by EGF. Am J Physiol Cell Physiol 294:C1362–C1370
O’Rourke JF, Dachs GU, Gleadle JM et al (1997) Hypoxia response elements. Oncology Res 9:327–332
Oppermann M, Mizel D, Kim SM et al (2007) Renal function in mice with targeted disruption of the A isoform of the Na–K–2Cl co-transporter. J Am Soc Nephrol 18:440–448
Pace AJ, Lee E, Athirakul K et al (2000) Failure of spermatogenesis in mouse lines deficient in the Na+–K+–2Cl− cotransporter. J Clin Invest 105:441–450
Pacheco-Alvarez D, Cristóbal PS, Meade P et al (2006) The Na+:Cl− cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J Biol Chem 281:28755–28763
Pallesen LT, Vaegter CB (2012) Sortilin and SorLA regulate neuronal sorting of trophic and dementia-linked proteins. Mol Neurobiol 45:379–387
Paredes A, Plata C, Rivera M et al (2006) 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 290:F1094–F1102
Payne JA, Forbush BI (1994) Alternatively spliced isoforms of the putative renal Na–K–Cl cotransporter are differentially distributed within the rabbit kidney. Proc Natl Acad Sci U S A 91:4544–4548
Pellikainen JM, Kosma VM (2007) Activator protein-2 in carcinogenesis with a special reference to breast cancer—a mini review. Int J Cancer 120:2061–2067
Peti-Peterdi J, Harris RC (2010) Macula densa sensing and signaling mechanisms of renin release. J Am Soc Nephrol 21:1093–1096
Piechotta K, Lu J, Delpire E (2002) Cation–chloride cotransporters interact with the stress-related kinases SPAK and OSR1. J Biol Chem 277:50812–50819
Plotkin MD, Kaplan MR, Peterson LN et al (1997) Expression of the Na+–K+–2Cl− cotransporter BSC2 in the nervous system. Am J Physiol Cell Physiol 272:C173–C183
Plotkin MD, Snyder EY, Hebert SC et al (1997) Expression of the Na–K–2Cl cotransporter is developmentally regulated in postnatal rat brains: a possible mechanism underlying GABA’s excitatory role in immature brain. J Neurobiol 33:781–795
Ponce-Coria J, Gagnon KB, Delpire E (2012) Calcium-binding protein 39 facilitates molecular interaction between Ste20p proline alanine-rich kinase and oxidative stress response 1 monomers. Am J Physiol Cell Physiol 303:C1198–C1205
Randall J, Thorne T, Delpire E (1997) Partial cloning and characterization of Slc12a2: the gene encoding the secretory Na+–K+–2Cl− cotransporter. Am J Physiol Cell Physiol 273:C1267–C1277
Reiche J, Theilig F, Rafiqi FH et al (2010) SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na(+)–K(+)–Cl(−) cotransporter 2. Mol Cell Biol 30:3027–3037
Reisert J, Lai J, Yau KW et al (2005) Mechanism of the excitatory Cl− response in mouse olfactory receptor neurons. Neuron 45:553–561
Richardson C, Sakamoto K, de los Heros P et al (2011) Regulation of the NKCC2 ion cotransporter by SPAK–OSR1-dependent and -independent pathways. J Cell Sci 124:789–800
Russell JM (1983) Cation-coupled chloride influx in squid axon. Role of potassium and stoichiometry of the transport process. J Gen Physiol 81:909–925
Schlatter E, Salomonsson M, Persson AE et al (1989) Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na + 2Cl − K + cotransport. Pflugers Arch 414:286–290
Simard CF, Brunet GM, Daigle ND et al (2004) Self-interacting domains in the C terminus of a cation-Cl − cotransporter described for the first time. J Biol Chem 279:40769–40777
Simon DB, Karet FE, Hamdan JM et al (1996) Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na–K–2Cl cotransporter NKCC2. Nature Gen 13:183–188
Smith L, Smallwood N, Altman A et al (2008) PKCdelta acts upstream of SPAK in the activation of NKCC1 by hyperosmotic stress in human airway epithelial cells. J Biol Chem 283:22147–22156
Somasekharan S, Tanis J, Forbush B (2012) Loop diuretic and ion-binding residues revealed by scanning mutagenesis of transmembrane helix 3 (TM3) of Na–K–Cl cotransporter (NKCC1). J Biol Chem 287:17308–17317
Starremans PG, Kersten FF, Knoers NV et al (2003) Mutations in the human Na–K–2Cl cotransporter (NKCC2) identified in Bartter syndrome type I consistently result in nonfunctional transporters. J Am Soc Nephrol 14:1419–1426
Sung K-W, Kirby M, McDonald MP et al (2000) Abnormal GABAA-receptor mediated currents in dorsal root ganglion neurons isolated from Na–K–2Cl cotransporter null mice. J Neurosci 20:7531–7538
Takahashi N, Chernavvsky DR, Gomez RA et al (2000) Uncompensated polyuria in a mouse model of Bartter’s syndrome. Proc Natl Acad Sci U S A 97:5434–5439
Trepiccione F, Zacchia M, Capasso G (2012) The role of the kidney in salt-sensitive hypertension. Clin Exp Nephrol 16:68–72
Vanderwinden JM, Liu H, De Laet MH et al (1996) Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis. Gastroenterology 111:279–288
Vanderwinden JM, Rumessen JJ, Liu H et al (1996) Interstitial cells of Cajal in human colon and in Hirschsprung’s disease. Gastroenterology 111:901–910
Vetter DE, Mann JR, Wangemann P et al (1996) Inner ear defects induced by null mutation of the isk gene. Neuron 17:1251–1264
Vibat CR, Holland MJ, Kang JJ et al (2001) Quantitation of Na+–K+–2Cl− cotransport splice variants in human tissues using kinetic polymerase chain reaction. Anal Biochem 298:218–230
Vitari AC, Deak M, Morrice NA et al (2005) The WNK1 and WNK4 protein kinases that are mutated in Gordon’s hypertension syndrome, phosphorylate and active SPAK and OSR1 protein kinases. Biochem J 391:17–24
Wagner CA, Devuyst O, Bourgeois S et al (2009) Regulated acid–base transport in the collecting duct. Pfluegers Arch 458:137–156
Wedel T, Spiegler J, Soellner S et al (2002) Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon. Gastroenterology 123:1459–1467
Weiner ID, Verlander JW (2011) Role of NH3 and NH4+ transporters in renal acid–base transport. Am J Physiol Renal Physiol 300:F11–F23
Welker P, Böhlick A, Mutig K et al (2008) Renal Na+–K+–Cl− cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent. Am J Physiol Renal Physiol 295:F789–F802
Willis WD (1999) Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res 124:395–421
Wong FH, Chen JS, Reddy V et al (2012) The amino acid–polyamine–organocation superfamily. J Mol Microbiol Biotechnol 22:105–113
Wouters M, De Laet A, Ver Donck L et al (2006) Subtractive hybridization unravels a role for the ion co-transporter NKCC1 in the murine intestinal pacemaker. Am J Physiol Gastrointest Liver Physiol 290:G1219–G1227
Wu Q, Delpire E, Hebert SC et al (1998) Functional demonstration of Na–K–2Cl cotransporter activity in isolated, polarized choroid plexus cells. Am J Physiol Cell Physiol 275:C1565–C1572
Xu J-C, Lytle C, Zhu TT et al (1994) Molecular cloning and functional expression of the bumetanide-sensitive Na–K–2Cl cotransporter. Proc Natl Acad Sci U S A 91:2201–2205
Yamamoto Y, Matsubara A, Ishii K et al (2002) Localization of gamma-aminobutyric acid A receptor subunits in the rat spiral ganglion and organ of Corti. Acta Otolaryngol 122:709–714
Yamashita A, Singh SK, Kawate T et al (2005) Crystal structure of a bacterial homologue of Na+/Cl−−dependent neurotransmitter transporters. Nature 437:215–223
Yang T, Huang YG, Singh I et al (1996) Localization of bumetanide- and thiazide-sensitive Na–K–Cl cotransporters along the rat nephron. Am J Physiol (Renal Physiol) 271:F931–F939
Yang SS, Lo YF, Wu CC et al (2010) SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol 21:1868–1877
Zaarour N, Defontaine N, Demaretz S et al (2011) Secretory carrier membrane protein 2 regulates exocytic insertion of NKCC2 into the cell membrane. J Biol Chem 286:9489–9502
Zdebik AA, Wangemann P, Jentsch TJ (2009) Potassium ion movement in the inner ear: insights from genetic disease and mouse models. Physiology (Bethesda) 24:307–316
Zhang LL, Delpire E, Vardi N (2007) NKCC1 does not accumulate chloride in developing retinal neurons. J Neurophysiol 98:266–277
Zhu L, Polley N, Mathews GC et al (2008) NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus. Epilepsy Res 79:201–212
Acknowledgments
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-093501 and the National Institute of General Medical Sciences Grant GM074771 (to E. Delpire). The authors wish to thank Dr. Kenneth Gagnon (University of Saskatchewan, Saskatoon, SK, Canada) for reading the manuscript.
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This article is published as part of the Special Issue on Sodium-dependent transporters in health and disease.
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Markadieu, N., Delpire, E. Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Arch - Eur J Physiol 466, 91–105 (2014). https://doi.org/10.1007/s00424-013-1370-5
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DOI: https://doi.org/10.1007/s00424-013-1370-5