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Na+-K+-2Cl− Cotransporter

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Studies of Epithelial Transporters and Ion Channels

Part of the book series: Physiology in Health and Disease ((PIHD))

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Abstract

The conceptual breakthrough that the energy of the Na+ gradient generated by the Na+/K+ ATPase (pump) could be used as the driving force for another membrane transport protein has led to the functional and molecular identification of multiple secondary active transporters. We have organized this chapter to address the expression, function, regulation, and evolutionary importance of the two isoforms of the electroneutral sodium–potassium–chloride cotransporter (NKCC). The combination of basolateral expression of the sodium–potassium pump and NKCC1 in various non-renal epithelial results in salt and water secretion, whereas basolateral expression of the pump with an apical expression of NKCC2 in the thick ascending limb of Henle of the kidney nephron results in salt and water reabsorption. NKCCs are regulated by phosphorylation of specific serine/threonine residues in their cytosolic amino-terminal domains, and the evolutionary conservation of these cotransporters from protists to humans confirms their vital role in cellular and whole-organism physiology.

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References

  • Aickin CC, Betz WJ, Harris GL (1989) Intracellular chloride and the mechanism for its accumulation in rat lumbrical muscle. J Physiol 411:437–455

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akar F, Skinner E, Klein JD, Jena M, Paul RJ, O’Neill WC (1999) Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl− cotransporter in rat aorta. Am J Phys 276:C1383–C1390

    CAS  Google Scholar 

  • Altamirano AA, Breitwieser GE, Russel JM (1988) Vanadate and fluoride effects on Na-K-Cl cotransport in squid giant axon. Am J Phys 254:C582–C586

    CAS  Google Scholar 

  • Alvarez-Leefmans FJ, Gamiño SM, Giraldez F, Nogueron I (1988) Intracellular chloride regulation in amphibian dorsal root ganglion neurons studied with ionselective microelectrodes. J Physiol Lond 406:225–246

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ando M, Wong MK, Takei Y (2014) Mechanisms of guanylin action on water and ion absorption at different regions of seawater eel intestine. Am J Physiol Regul Integr Comp Physiol 307:R653–R663

    CAS  PubMed  Google Scholar 

  • Austin T, Nannemann DP, Deluca SL, Meiler J, Delpire E (2014) In silico analysis and experimental verification of OSR1 kinase - peptide interaction. J Struct Biol 187:58–65

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bajwa PJ, Lee JW, Straus DS, Lytle C (2009) Activation of PPARγ by rosiglitazone attenuates intestinal Cl− secretion. Am J Physiol Gastrointest Liver Physiol 297:G82–G97

    CAS  PubMed  Google Scholar 

  • Bartter FC, Pronove P, Gill JRJ, Maccardle RC (1962) Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33:811–828

    CAS  PubMed  Google Scholar 

  • Boyden LM et al (2012) Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:98–102

    CAS  PubMed  PubMed Central  Google Scholar 

  • Canessa M, Brugnara C, Cusi D, Tosteson DC (1986) Modes of operation and variable stoichiometry of the furosemide-sensitive Na and K fluxes in human red cells. J Gen Physiol 87:113–142

    CAS  PubMed  Google Scholar 

  • Carmosino M, Giménez I, Caplan M, Forbush B (2008) Exon loss accounts for differential sorting of Na-K-Cl Cotransporters in polarized epithelial cells. Mol Biol Cell 19:4341–4351

    CAS  PubMed  PubMed Central  Google Scholar 

  • Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, Pfeifer K (2001) Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen syndrome. Proc Natl Acad Sci USA 98:2526–2531

    CAS  PubMed  PubMed Central  Google Scholar 

  • Castañeda-Bueno M, Cervantes-Pérez LG, Vázquez N, Uribe N, Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR, Gamba G (2012) Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci USA 109:7929–7934

    PubMed  PubMed Central  Google Scholar 

  • Cheng SX (2012) Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system. Am J Physiol Gasterointest Liver Physiol 303:G60–G70

    CAS  Google Scholar 

  • Christensen HL, Nguyen AT, Pedersen FD, Damkier HH (2013) Na(+) dependent acid-base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol 4:1–10

    Google Scholar 

  • Cook DI, Young JA (1989) Fluid and electrolyte secretion by salivary glands. In: Handbook of physiology. The gastrointestinal system. Salivary, pancreatic, gastric and hepatobiliary secretion. American Physiological Society, Bethesda, MD, pp 1–23

    Google Scholar 

  • Crane RK (1965) Na+-dependent transport in the intestine and other animal tissues. Fed Proc 24:1000–1006

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Das S, Jayaratne R, Barrett KE (2018) The role of ion transporters in the pathophysiology of infectious diarrhea. Cell Mol Gastroenterol Hepatol 6:33–45

    PubMed  PubMed Central  Google Scholar 

  • Delpire E (2009) The mammalian family of Sterile20p-like protein kinases. Pflügers Arch 458:953–967

    CAS  PubMed  Google Scholar 

  • Delpire E, Gagnon KB (2008) SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J 409:321–331

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Delpire E, Rauchman MI, Beier DR, Hebert SC, Gullans SR (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

    CAS  PubMed  Google Scholar 

  • Delpire E, Lu J, England R, Dull C, Thorne T (1999) Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet 22:192–195

    CAS  PubMed  Google Scholar 

  • Delpire E, Wolfe L, Flores B, Koumangoye R, Schornak CC, Omer S, Pusey B, Lau C, Markello T, Adams DR (2016) A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1. Cold Spring Harb Mol Case Studies 2:a001289

    Google Scholar 

  • Dixon MJ, Gazzard J, Chaudhry SS, Sampson N, Schulte BA, Steel KP (1999) Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice. Hum Mol Genet 8:1579–1584

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Evans RL, Park K, Turner RJ, Watson GE, Nguyen H-V, Dennett MR, Hand AR, Flagella M, Shull GE, Melvin JE (2000) Severe impairment of salivation in Na+/K+/2Cl− cotransporter (NKCC1)-deficient mice. J Biol Chem 275:26720–26726

    CAS  PubMed  Google Scholar 

  • Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA, Andringa A, Gawenis LR, Kramer J, Duffy JJ, Doetschman T, Lorenz JN, Yamoah EN, Cardell EL, Shull GE (1999) Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem 274:26946–26955

    CAS  PubMed  Google Scholar 

  • Flemmer AW, Gimenez I, Dowd BF, Darman RB, Forbush B (2002) Activation of the Na-K-Cl cotransporter NKCC1 detected with a phospho-specific antibody. J Biol Chem 277:37551–37558

    CAS  PubMed  Google Scholar 

  • Gagnon KB, Delpire E (2010) Molecular determinants of hyperosmotically activated NKCC1-mediated K+/K+ exchange. J Physiol Lond 588:3385–3396

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gagnon KB, Delpire E (2012) Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiol Rev 92:1577–1617

    CAS  PubMed  Google Scholar 

  • Gagnon KB, Delpire E (2013a) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically-engineered mouse knockouts. Am J Physiol Cell Physiol 304:C693–C714

    PubMed  PubMed Central  Google Scholar 

  • Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee W-S, Hediger M, Hebert SC (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

    CAS  PubMed  Google Scholar 

  • Geck P, Pietrzyk C, Burckhardt B-C, Pfeiffer B, Heinz E (1980) Electrically silent cotransport of Na+ , K+ and Cl− in Ehrlich cells. Biochim Biophys Acta 600:432–447

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giménez I, Isenring P, Forbush B (2002) Spatially distributed alternative splice variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions. J Biol Chem 277:8767–8770

    PubMed  Google Scholar 

  • Ginns SM, Knepper MA, Ecelbarger CA, Terris J, He X, Coleman RA, Wade JB (1996) Immunolocalization of the secretory isoform of Na-K-Cl cotransporter in rat renal intercalated cells. J Am Soc Nephrol 7:2533–2542

    CAS  PubMed  Google Scholar 

  • Gosmanov AR, Lindinger MI, Thomason DB (2003) Riding the tides: K+ concentration and volume regulation by muscle Na+-K+-2Cl− cotransport activity. News Physiol Sci 18:196–200

    CAS  PubMed  Google Scholar 

  • Gregoriades JMC, Madaris A, Francisco J, Alvarez FJ, Alvarez-Leefmans FJ (2019) Genetic and pharmacologic inactivation of apical NKCC1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter. Am J Physiol Cell Physiol. https://doi.org/10.1152/ajpcell.00026.2018

  • Grimm PR, Taneja TK, Liu J, Coleman R, Chen YY, Delpire E, Wade JB, Welling PA (2012) SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem 287:37673–37690

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grubb BR, Lee E, Pace AJ, Koller BH, Boucher RC (2000) Intestinal ion transport in NKCC1-deficient mice. Am J Physiol Gastrointest Liver Physiol 279:G707–G718

    CAS  PubMed  Google Scholar 

  • Hall AC, Ellory JC (1985) Measurement and stoichiometry of bumetanide-sensitive (2Na:1K:3Cl) cotransport in ferret red cells. J Membrane Biol 85:205–213

    CAS  Google Scholar 

  • Halonen J, Hinton AS, Frisina RD, Ding B, Zhu X, Walton JP (2016) Long-term treatment with aldosterone slows the progression of age-related hearing loss. Hear Res 336:63–71

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hiroi J, Yasumasu S, McCormick SD, Hwang PP, Kaneko T (2008) Evidence for an apical Na-Cl cotransporter involved in ion uptake in a teleost fish. J Exp Biol 211:2584–2599

    CAS  PubMed  Google Scholar 

  • Hoffman JF, Kregenow FM (1966) The characterization of new energy dependent cation transport processes in red blood cells. Ann N Y Acad Sci 137:566–576

    CAS  PubMed  Google Scholar 

  • Howard PA, Dunn MI (1997) Severe musculoskeletal symptoms during continuous infusion of bumetanide. Chest 111:359–364

    CAS  PubMed  Google Scholar 

  • Hunziker W, Fumey C (1994) A di-leucine motif mediates endocytosis and basolateral sorting of macrophage IgG Fc receptors in MDCK cells. EMBO J 13:2963–2969

    CAS  PubMed  PubMed Central  Google Scholar 

  • Igarashi P, Whyte DA, Li K, Nagami GT (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

    CAS  PubMed  Google Scholar 

  • Ikeda K, Oshima T, Hidaka H, Takasaka T (1997) Molecular and clinical implications of loop diuretic ototoxicity. Hearing Res 107:1–8

    CAS  Google Scholar 

  • Kaplan MR, Plotkin MD, Brown D, Hebert SC, Delpire E (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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT (2017) Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med 23:997–1003

    CAS  PubMed  Google Scholar 

  • Koumangoye R, Omer S, Delpire E (2018) Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells. Am J Physiol Cell Physiol 315:C258–C276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koumangoye R, Omer S, Delpire E (2019) A dileucine motif in the C-terminal domain of NKCC1 targets the cotransporter to the plasma membrane. Am J Physiol Cell Physiol. https://doi.org/10.1152/ajpcell.00023.2019

  • Kregenow FM (1971a) The response of duck erythrocytes to nonhemolytic hypotonic media. Evidence for a volume-controlling mechanism. J Gen Physiol 58:372–395

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kregenow FM (1971b) The response of duck erythrocytes to hypertonic media. Further evidence for a volume-controlling mechanism. J Gen Physiol 58:396–411

    CAS  PubMed  PubMed Central  Google Scholar 

  • Laird JM, Garcia-Nicas E, Delpire EJ, Cervero F (2004) Presynaptic inhibition and spinal pain processing in mice: a possible role of the NKCC1 cation-chloride co-transporter in hyperalgesia. Neurosci Lett 361:200–203

    CAS  PubMed  Google Scholar 

  • Liedkte CM (1992) Electrolyte transport in the epithelium of pulmonary segments of normal and cystic fibrosis lung. FASEB J 6:3076–3084

    Google Scholar 

  • Lin LY, Weng CF, Hwang PP (2001) Regulation of drinking rate in euryhaline tilapia larvae (Oreochromis mossambicus) during salinity challenges. Physiol Biochem Zool 74:171–177

    CAS  PubMed  Google Scholar 

  • Lin SH, Yu IS, Jiang ST, Lin SW, Chu P, Chen A, Sytwu HK, Sohara E, Uchida S, Sasaki S, Yang SS (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 USA 108:17538–17543

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lytle C (1998) A volume-sensitive protein kinase regulates the Na-K-2Cl cotransporter in duck red blood cells. Am J Physiol Cell Physiol 274:C1002–C1010

    CAS  Google Scholar 

  • Lytle C, Forbush BI (1992a) Na-K-Cl cotransport in the shark rectal gland. II. Regulation in isolated tubules. Am J Physiol Cell Physiol 262:C1009–C10117

    CAS  Google Scholar 

  • Lytle C, Forbush BI (1992b) The Na-K-Cl cotransport protein of shark rectal gland. II. Regulation by direct phosphorylation. J Biol Chem 267:25438–25443

    CAS  PubMed  Google Scholar 

  • Lytle C, McManus TJ, Haas M (1998) A model of Na-K-2Cl cotransport based on ordered ion binding and glide symmetry. Am J Phys 274:C299–C309

    CAS  Google Scholar 

  • Macnamara EF, Koehler AE, D’Souza P, Estwick T, Lee P, Vezina G, Network MUD, Fauni H, Braddock SR, Torti E, Holt JM, Sharma P, Malicdan MCV, Tifft CJ (2019) Kilquist syndrome: a novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2. Hum Mut 40(5):532–538

    CAS  PubMed  Google Scholar 

  • McCormick JA, Mutig K, Nelson JH, Saritas T, Hoorn EJ, Yang C-L, Rogers S, Curry J, Delpire E, Bachmann S, Ellison DH (2011) A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metab 14:352–364

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meyer JW, Flagella M, Sutliff RL, Lorenz JN, Nieman ML, Weber CS, Paul RJ, Shull GE (2002) Decreased blood pressure and vascular smooth muscle tone in mice lacking basolateral Na(+)-K(+)-2Cl(−) cotransporter. Am J Physiol Heart Circ Physiol 283:H1846–H1855

    CAS  PubMed  Google Scholar 

  • Mykoniatis A, Shen L, Fedor-Chaiken M, Tang J, Tang X, Worrell RT, Delpire E, Turner JR, Matlin KS, Bouyer P, Matthews JB (2010) Phorbol 12-myristate 13-acetate-induced endocytosis of the Na-K-2Cl cotransporter in MDCK cells is associated with a clathrin-dependent pathway. Am J Physiol Cell Physiol 298:C85–C97

    CAS  PubMed  Google Scholar 

  • Ohta A, Rai T, Yui N, Chiga M, Yang SS, Lin SH, Sohara E, Sasaki S, Uchida S (2008) Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure. Hum Mol Genet 18:3978–3986

    Google Scholar 

  • Orlov SN, Tremblay J, Hamet P (1996) Bumetanide-sensitive ion fluxes in vascular smooth muscle cells: lack of functional Na+, K+, 2 Cl− cotransport. J Membr Biol 153:125–135

    CAS  PubMed  Google Scholar 

  • Pace AJ, Lee E, Athirakul K, Coffman TM, O’Brien DA, Koller BH (2000) Failure of spermatogenesis in mouse lines deficient in the Na+-K+-2Cl− cotransporter. J Clin Invest 105:441–450

    CAS  PubMed  PubMed Central  Google Scholar 

  • Palfrey HC, O’Donnell ME (1992) Characteristics and regulation of the Na/K/2Cl cotransporter. Cell Physiol Biochem 2:293–307

    CAS  Google Scholar 

  • Panet R, Markus M, Atlan H (1994) Bumetanide and furosemide inhibited vascular endothelial cell proliferation. J Cell Physiol 158:121–127

    CAS  PubMed  Google Scholar 

  • Panet R, Marcus M, Atlan H (2000) Overexpression of the Na+/K+/Cl− cotransporter gene induces cell proliferation and phenotypic transformation in mouse fibroblasts. J Cell Physiol 182:109–118

    CAS  PubMed  Google Scholar 

  • 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 USA 91:4544–4548

    CAS  PubMed  PubMed Central  Google Scholar 

  • Payne JA, Xu J-C, Haas M, Lytle CY, Ward D, Forbush BI (1995) Primary structure, functional expression, and chromosome localization of the bumetanide sensitive Na-K-Cl cotransporter in human colon. J Biol Chem 270:17977–17985

    CAS  PubMed  Google Scholar 

  • Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ (2014) Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 7:ra41

    PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Piechotta K, Garbarini NJ, England R, Delpire E (2003) 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 278:52848–52856

    CAS  PubMed  Google Scholar 

  • Pressler CA, Heinzinger J, Jeck N, Waldegger P, Pechmann U, Reinalter S, Konrad M, Beetz R, Seyberth HW, Waldegger S (2006) Late-onset manifestation of antenatal Bartter syndrome as a result of residual function of the mutated renal Na+-K+-2Cl− co-transporter. J Am Soc Nephrol 17:2136–2142

    CAS  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Resta-Lenert S, Truong F, Barrett KE, Eckmann L (2001) Inhibition of epithelial chloride secretion by butyrate: role of reduced adenylyl cyclase expression and activity. Am J Physiol Cell Physiol 281:C1837–C1849

    CAS  PubMed  Google Scholar 

  • Rocha AS, Kudo LH (1990) Atrial peptide and cGMP effects on NaCl transport in inner medullary collecting duct. Am J Physiol (Renal Fluid Electrolyte Physiol) 259:F258–F268

    CAS  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Rybak LP (1993) Ototoxicity of loop diuretics. Otolaryngol Clin N Am 26:829–844

    CAS  Google Scholar 

  • Seale AP, Stagg JJ, Yamaguchi Y, Breves JP, Soma S, Watanabe S, Kaneko T, Cnaani A, Harpaz S, Lerner DT, Grau EG (2014) Effects of salinity and prolactin on gene transcript levels of ion transporters, ion pumps and prolactin receptors in Mozambique tilapia intestine. Gen Comp Endocrinol 206:146–154

    CAS  PubMed  Google Scholar 

  • Silva P, Stoff J, Field M, Fine L, Forrest JN, Epstein FH (1977) Mechanism of active chloride secretion by shark rectal gland: role of Na-K-ATPase in chloride transport. Am J Physiol (Renal Fluid Electrolyte Physiol) 233:F298–F306

    CAS  Google Scholar 

  • Simon DB, Karet FE, Rodriquez-Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP (1996) Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14:152–156

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sonnenberg H, Honrath U, Wilson DR (1990) In vivo microperfusion of inner medullary collecting duct in rats: effect of amiloride and ANF. Am J Physiol (Renal Fluid Electrolyte Physiol) 259:F222–F226

    CAS  Google Scholar 

  • Soybel DI, Gullans SR, Maxwell F, Delpire E (1995) Role of basolateral Na-K-Cl cotransport in HCl secretion by amphibian gastric mucosa. Am J Physiol Cell Physiol 269:C242–C249

    CAS  Google Scholar 

  • Steffensen AB, Oernbo EK, Stoica A, Gerkau NJ, Barbuskaite D, Tritsaris K, Rose CR, MacAulay N (2018) Cotransporter-mediated water transport underlying cerebrospinal fluid formation. Nat Commun 9:2167

    PubMed  PubMed Central  Google Scholar 

  • Sung K-W, Kirby M, McDonald MP, Lovinger DM, Delpire E (2000) Abnormal GABAA-receptor mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci 20:7531–7538

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang J, Bouyer P, Mykoniatis A, Buschmann M, Matlin KS, Matthews JB (2010) Activated PKCδ and PKCε inhibit epithelial chloride secretion response to cAMP via inducing internalization of the Na+-K+-2Cl− cotransporter NKCC1. J Biol Chem 285:34072–34085

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tasaki I, Spiropoulos CS (1959) Stria vascularis as source of endocochlear potential. J Neurophysiol 22:149–155

    CAS  PubMed  Google Scholar 

  • Tyson J, Tranebjaerg, L., Bellman, S., Wren, C., Taylor, J. F. N., Bathen, J., Aslaksen, B., Sorland, S. J., Lund, O., Malcolm, S., Pembrey, M., Bhattacharya, S., Bitner-Glindzicz, M. (1997) IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet 61:2179–2185

    Google Scholar 

  • Vaduganathan M, Allegretti AS, Manchette AM, Patel SS, Olson KR, Bazari H (2013) Intravenous moderate-dose bumetanide continuous infusion and severe musculoskeletal pain. Int J Cardiol 168:e29–e31

    PubMed  Google Scholar 

  • Vetter DE, Mann JR, Wangemann P, Liu J, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J (1996) Inner ear defects induced by null mutation of the isk gene. Neuron 17:1251–1264

    CAS  PubMed  Google Scholar 

  • Villa F, Goebel J, Rafiqi FH, Deak M, Thastrup J, Alessi DR, van Aalten DMF (2007) Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep 8:839–845

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vitari AC, Thastrup J, Rafiqi FH, Deak M, Morrice NA, Karlsson HK, Alessi DR (2006) Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J 397:223–231

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y et al (2009) Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA 106:226–231

    CAS  PubMed  Google Scholar 

  • Wiener H, van Os CH (1989) Rabbit distal colon epithelium: II. Characterization of (Na+,K+,Cl-)-cotransport and [3H]-bumetanide binding. J Membr Biol 110:163–174

    CAS  PubMed  Google Scholar 

  • Wong FH, Chen JS, Reddy V, Day JL, Shlykov MA, Wakabayashi ST, Saier MHJ (2012) The amino acid-polyamine-organocation superfamily. J Mol Microbiol Biotechnol 22:105–113

    PubMed  Google Scholar 

  • Wouters M, De Laet A, Ver Donck L, Delpire E, van Bogaert PP, Timmermans JP, de Kerchove d’Exaerde A, Smans K, Vanderwinden JM (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

    CAS  PubMed  Google Scholar 

  • Xu J-C, Lytle C, Zhu TT, Payne JA, Benz EJ, Forbush BI (1994) Molecular cloning and functional expression of the bumetanide-sensitive Na-K-2Cl cotransporter. Proc Natl Acad Sci USA 91:2201–2205

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E (2005) Crystal structure of a bacterial homologue of Na+/Cl−-dependent neurotransmitter transporters. Nature 437:215–223

    CAS  PubMed  Google Scholar 

  • Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S (2007) Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab 5:331–344

    CAS  PubMed  Google Scholar 

  • Yang SS, Lo YF, Wu CC, Lin SW, Yeh CJ, Chu P, Sytwu HK, Uchida S, Sasaki S, Lin SH (2010) SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol 21:1868–1877

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zeidel ML, Kikeri D, Silva P, Burrowes M, Brenner BM (1988) Atrial natriuretic peptides inhibit conductive sodium uptake by rabbit inner medullary collecting duct cells. J Clin Invest 82:1067–1074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu MH, Sung TS, Kurahashi M, O'Kane LE, O’Driscoll K, Koh SD, Sanders KM (2016) Na+-K+-Cl− cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 311:G1037–G1046

    PubMed  PubMed Central  Google Scholar 

Selected Readings

  • Gagnon KB, Delpire E (2013b) Physiology of Slc12 transporters: lessons from inherited human genetic mutations and genetically-engineered mouse knockouts. Am J Physiol Cell Physiol 304:C693–C714

    PubMed  PubMed Central  Google Scholar 

  • Gamba G (2009) The sodium-dependent chloride cotransporters. In: Alvarez-Leefmans FJ, Delpire E (eds) Physiology and pathology of chloride transporters and channels in the nervous system. Academic Press (Elsevier), London, pp 307–332

    Google Scholar 

  • Gamba G, Garbarini N, Delpire E (2009) Regulation of cation-chloride cotransporters. In: Alvarez-Leefmans FJ, Delpire E (eds) Physiology and pathology of chloride transporters and channels in the nervous system. Academic Press (Elsevier), London, pp 357–382

    Google Scholar 

  • Russell JM (2000) Sodium-potassium-chloride cotransport. Physiol Rev 80:212–276

    Google Scholar 

  • Russell JM (2009) Sodium-coupled chloride cotransporters: Discovery and newly emerging concepts. In: Alvarez-Leefmans FJ, Delpire E (eds) Physiology and pathology of chloride transporters and channels in the nervous system. Academic Press (Elsevier), London, pp 17–26

    Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Eric Delpire

  2. Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA

    Kenneth B. Gagnon

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  1. Eric Delpire
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  2. Kenneth B. Gagnon
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Correspondence to Eric Delpire .

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Editors and Affiliations

  1. Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, Otago, New Zealand

    Kirk L. Hamilton

  2. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Daniel C. Devor

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Delpire, E., Gagnon, K.B. (2020). Na+-K+-2Cl− Cotransporter. In: Hamilton, K.L., Devor, D.C. (eds) Studies of Epithelial Transporters and Ion Channels. Physiology in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-55454-5_2

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