Abstract
The SLC9 gene family encodes Na+/H+ exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46]. NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na+ and HCO3 − and thus for whole body volume and acid–base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease. However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases.
Similar content being viewed by others
References
Alexander RT, Jaumouille V, Yeung T, Furuya W, Peltekova I, Boucher A, Zasloff M, Orlowski J, Grinstein S (2011) Membrane surface charge dictates the structure and function of the epithelial Na+/H + exchanger. Embo J 30(4):679–691
Amin MR, Malakooti J, Sandoval R, Dudeja PK, Ramaswamy K (2006) IFN-gamma and TNF-alpha regulate human NHE3 gene expression by modulating the Sp family transcription factors in human intestinal epithelial cell line C2BBe1. Am J Physiol Cell Physiol 291(5):C887–896
Arena EA, Longo WE, Roberts KE, Geibel P, Nateqi J, Brandstetter M, Geibel JP (2012) Functional role of NHE4 as a pH regulator in rat and human colonic crypts. Am J Physiol Cell Physiol 302(2):C412–418
Attaphitaya S, Nehrke K, Melvin JE (2001) Acute inhibition of brain-specific Na(+)/H(+) exchanger isoform 5 by protein kinases A and C and cell shrinkage. Am J Physiol Cell Physiol 281(4):C1146–1157
Attaphitaya S, Park K, Melvin JE (1999) Molecular cloning and functional expression of a rat Na+/H+ exchanger (NHE5) highly expressed in brain. J Biol Chem 274(7):4383–4388
Bachmann O, Riederer B, Rossmann H, Groos S, Schultheis PJ, Shull GE, Gregor M, Manns MP, Seidler U (2004) The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation. Am J Physiol Gastrointest Liver Physiol 287(1):G125–133
Baird NR, Orlowski J, Szabo EZ, Zaun HC, Schultheis PJ, Menon AG, Shull GE (1999) Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brain. J Biol Chem 274(7):4377–4382
Banday AA, Lokhandwala MF (2011) Angiotensin II-mediated biphasic regulation of proximal tubular Na+/H+ exchanger 3 is impaired during oxidative stress. Am J Physiol Renal Physiol 301(2):F364–370
Banday AA, Lokhandwala MF (2011) Oxidative stress causes renal angiotensin II type 1 receptor upregulation, Na+/H+ exchanger 3 overstimulation, and hypertension. Hypertension 57(3):452–459
Battaglino RA, Pham L, Morse LR, Vokes M, Sharma A, Odgren PR, Yang M, Sasaki H, Stashenko P (2007) NHA-oc/NHA2: a mitochondrial cation–proton antiporter selectively expressed in osteoclasts. Bone 42: 180–192
Battaglino RA, Pham L, Morse LR, Vokes M, Sharma A, Odgren PR, Yang M, Sasaki H, Stashenko P (2008) NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts. Bone 42(1):180–192
Baum M, Twombley K, Gattineni J, Joseph C, Wang L, Zhang Q, Dwarakanath V, Moe OW (2012) Proximal tubule Na+/H+ exchanger activity in adult NHE8-/-, NHE3-/-, and NHE3-/-/NHE8-/- mice. Am J Physiol Renal Physiol 303(11):F1495–1502
Baumgartner M, Patel H, Barber DL (2004) Na(+)/H(+) exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes. Am J Physiol Cell Physiol 287(4):C844–850
Becker AM, Zhang J, Goyal S, Dwarakanath V, Aronson PS, Moe OW, Baum M (2007) Ontogeny of NHE8 in the rat proximal tubule. Am J Physiol Renal Physiol 293(1):F255–261
Bell SM, Schreiner CM, Schultheis PJ, Miller ML, Evans RL, Vorhees CV, Shull GE, Scott WJ (1999) Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Physiol 276(4 Pt 1):C788–795
Biemesderfer D, Reilly RF, Exner M, Igarashi P, Aronson PS (1992) Immunocytochemical characterization of Na(+)-H+ exchanger isoform NHE-1 in rabbit kidney. Am J Physiol 263(5 Pt 2):F833–840
Biemesderfer D, Rutherford PA, Nagy T, Pizzonia JH, Abu-Alfa AK, Aronson PS (1997) Monoclonal antibodies for high-resolution localization of NHE3 in adult and neonatal rat kidney. Am J Physiol 273(2 Pt 2):F289–299
Bobulescu IA, Di Sole F, Moe OW (2005) Na+/H+ exchangers: physiology and link to hypertension and organ ischemia. Curr Opin Nephrol Hypertens 14(5):485–494
Bookstein C, Musch MW, DePaoli A, Xie Y, Rabenau K, Villereal M, Rao MC, Chang EB (1996) Characterization of the rat Na+/H+ exchanger isoform NHE4 and localization in rat hippocampus. Am J Physiol 271(5 Pt 1):C1629–1638
Bourgeois S, Meer LV, Wootla B, Bloch-Faure M, Chambrey R, Shull GE, Gawenis LR, Houillier P (2010) NHE4 is critical for the renal handling of ammonia in rodents. J Clin Invest 120(6):1895–1904
Boyce SW, Bartels C, Bolli R, Chaitman B, Chen JC, Chi E, Jessel A, Kereiakes D, Knight J, Thulin L, Theroux P (2003) Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: results of the CABG surgery cohort of the GUARDIAN study. J Thorac Cardiovasc Surg 126(2):420–427
Brett CL, Donowitz M, Rao R (2005) Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 288(2):C223–239
Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC (1980) Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl J Med 302(14):772–776
Canessa M, Zerbini G, Laffel LM (1992) Sodium activation kinetics of red blood cell Na+/Li+ countertransport in diabetes: methodology and controversy. J Am Soc Nephrol 3(4 Suppl):S41–49
Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H + exchanger in metastasis. Nat Rev Cancer 5(10):786–795
Chambrey R, Achard JM, Warnock DG (1997) Heterologous expression of rat NHE4: a highly amiloride-resistant Na+/H+ exchanger isoform. Am J Physiol 272(1 Pt 1):C90–98
Chambrey R, St John PL, Eladari D, Quentin F, Warnock DG, Abrahamson DR, Podevin RA, Paillard M (2001) Localization and functional characterization of Na+/H+ exchanger isoform NHE4 in rat thick ascending limbs. Am J Physiol Renal Physiol 281(4):F707–717
Chambrey R, Warnock DG, Podevin RA, Bruneval P, Mandet C, Belair MF, Bariety J, Paillard M (1998) Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. Am J Physiol 275(3 Pt 2):F379–386
Charles JF, Coury F, Sulyanto R, Sitara D, Wu J, Brady N, Tsang K, Sigrist K, Tollefsen DM, He L, Storm D, Aliprantis AO (2012) The collection of NFATc1-dependent transcripts in the osteoclast includes numerous genes non-essential to physiologic bone resorption. Bone 51(5):902–912
Chen M, Sultan A, Cinar A, Yeruva S, Riederer B, Singh AK, Li J, Bonhagen J, Chen G, Yun C, Donowitz M, Hogema B, de Jonge H, Seidler U (2010) Loss of PDZ-adaptor protein NHERF2 affects membrane localization and cGMP- and [Ca2+]- but not cAMP-dependent regulation of Na+/H + exchanger 3 in murine intestine. J Physiol 588(Pt 24):5049–5063
Christianson AL, Stevenson RE, van der Meyden CH, Pelser J, Theron FW, van Rensburg PL, Chandler M, Schwartz CE (1999) X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J Med Genet 36(10):759–766
Clements-Jewery H, Sutherland FJ, Allen MC, Tracey WR, Avkiran M (2004) Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass. Br J Pharmacol 142(1):57–66
Counillon L, Pouyssegur J, Reithmeier RA (1994) The Na+/H + exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain. Biochemistry 33(34):10463–10469
Cox GA, Lutz CM, Yang CL, Biemesderfer D, Bronson RT, Fu A, Aronson PS, Noebels JL, Frankel WN (1997) Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91(1):139–148
D’Souza S, Garcia-Cabado A, Yu F, Teter K, Lukacs G, Skorecki K, Moore HP, Orlowski J, Grinstein S (1998) The epithelial sodium-hydrogen antiporter Na+/H+ exchanger 3 accumulates and is functional in recycling endosomes. J Biol Chem 273(4):2035–2043
Day JP, Wan S, Allan AK, Kean L, Davies SA, Gray JV, Dow JA (2008) Identification of two partners from the bacterial Kef exchanger family for the apical plasma membrane V-ATPase of Metazoa. J Cell Sci 121(Pt 15):2612–2619
de Silva MG, Elliott K, Dahl HH, Fitzpatrick E, Wilcox S, Delatycki M, Williamson R, Efron D, Lynch M, Forrest S (2003) Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype. J Med Genet 40(10):733–740
Deisl C, Simonin A, Anderegg M, Albano G, Kovacs G, Ackermann D, Moch H, Dolci W, Thorens B, AH M, Fuster DG (2013) Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in beta-cells. Proc Natl Acad Sci U S A 110(24):10004–10009
Demaurex N (2002) pH Homeostasis of cellular organelles. News Physiol Sci 17:1–5
Denker SP, Barber DL (2002) Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol 159(6):1087–1096
Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (2000) Direct binding of the Na–H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Mol Cell 6(6):1425–1436
Diering GH, Church J, Numata M (2009) Secretory carrier membrane protein 2 regulates cell-surface targeting of brain-enriched Na+/H+ exchanger NHE5. J Biol Chem 284(20):13892–13903
Diering GH, Mills F, Bamji SX, Numata M (2011) Regulation of dendritic spine growth through activity-dependent recruitment of the brain-enriched Na(+)/H(+) exchanger NHE5. Mol Biol Cell 22(13):2246–2257
Diering GH, Numata Y, Fan S, Church J, Numata M (2013) Endosomal acidification by Na,+/H+ exchanger NHE5 regulates TrkA cell-surface targeting and NGF-induced PI3K signaling. Mol Biol Cell 24: 3435–3448
Donowitz M, De La Horra C, Calonge ML, Wood IS, Dyer J, Gribble SM, De Medina FS, Tse CM, Shirazi-Beechey SP, Ilundain AA (1998) In birds, NHE2 is major brush-border Na+/H + exchanger in colon and is increased by a low-NaCl diet. Am J Physiol 274(6 Pt 2):R1659–1669
Donowitz M, Ming Tse C, Fuster D (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol Aspects Med 34(2–3):236–251
Fortuno A, Tisaire J, Lopez R, Bueno J, Diez J (1997) Angiotensin converting enzyme inhibition corrects Na+/H+ exchanger overactivity in essential hypertension. Am J Hypertens 10(1):84–93
Fuster DG, Zhang J, Shi M, Bobulescu IA, Andersson S, Moe OW (2008) Characterization of the sodium/hydrogen exchanger NHA2. J Am Soc Nephrol 19(8):1547–1556
Garbern JY, Neumann M, Trojanowski JQ, Lee VM, Feldman G, Norris JW, Friez MJ, Schwartz CE, Stevenson R, Sima AA (2010) A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain 133(Pt 5):1391–1402
Gawenis LR, Greeb JM, Prasad V, Grisham C, Sanford LP, Doetschman T, Andringa A, Miller ML, Shull GE (2005) Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger. J Biol Chem 280(13):12781–12789
Gawenis LR, Stien X, Shull GE, Schultheis PJ, Woo AL, Walker NM, Clarke LL (2002) Intestinal NaCl transport in NHE2 and NHE3 knockout mice. Am J Physiol Gastrointest Liver Physiol 282(5):G776–784
Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjoholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Stromme P (2008) SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet 82(4):1003–1010
Goyal S, Mentone S, Aronson PS (2005) Immunolocalization of NHE8 in rat kidney. Am J Physiol Renal Physiol 288(3):F530–538
Goyal S, Vanden Heuvel G, Aronson PS (2003) Renal expression of novel Na+/H+ exchanger isoform NHE8. Am J Physiol Renal Physiol 284(3):F467–473
Grinstein S, Woodside M, Waddell TK, Downey GP, Orlowski J, Pouyssegur J, Wong DC, Foskett JK (1993) Focal localization of the NHE-1 isoform of the Na+/H+ antiport: assessment of effects on intracellular pH. Embo J 12(13):5209–5218
Gu XQ, Yao H, Haddad GG (2001) Increased neuronal excitability and seizures in the Na(+)/H(+) exchanger null mutant mouse. Am J Physiol Cell Physiol 281(2):C496–503
Guan Y, Dong J, Tackett L, Meyer JW, Shull GE, Montrose MH (2006) NHE2 is the main apical NHE in mouse colonic crypts but an alternative Na +-dependent acid extrusion mechanism is upregulated in NHE2-null mice. Am J Physiol Gastrointest Liver Physiol 291(4):G689–699
Ha BG, Hong JM, Park JY, Ha MH, Kim TH, Cho JY, Ryoo HM, Choi JY, Shin HI, Chun SY, Kim SY, Park EK (2008) Proteomic profile of osteoclast membrane proteins: identification of Na+/H+ exchanger domain containing 2 and its role in osteoclast fusion. Proteomics 8(13):2625–2639
Hanner F, Chambrey R, Bourgeois S, Meer E, Mucsi I, Rosivall L, Shull GE, Lorenz JN, Eladari D, Peti-Peterdi J (2008) Increased renal renin content in mice lacking the Na+/H + exchanger NHE2. Am J Physiol Renal Physiol 294(4):F937–944
Hatch M, Freel RW (2008) Increased colonic sodium absorption in rats with chronic renal failure is partially mediated by AT1 receptor agonism. Am J Physiol Gastrointest Liver Physiol 295(2):G348–356
Haworth RS, Frohlich O, Fliegel L (1993) Multiple carbohydrate moieties on the Na+/H+ exchanger. Biochem J 289(Pt 3):637–640
Haworth RS, McCann C, Snabaitis AK, Roberts NA, Avkiran M (2003) Stimulation of the plasma membrane Na+/H+ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. J Biol Chem 278(34):31676–31684
Hayashi H, Aharonovitz O, Alexander RT, Touret N, Furuya W, Orlowski J, Grinstein S (2008) Na+/H + exchange and pH regulation in the control of neutrophil chemokinesis and chemotaxis. Am J Physiol Cell Physiol 294(2):C526–534
He P, Lee SJ, Lin S, Seidler U, Lang F, Fejes-Toth G, Naray-Fejes-Toth A, Yun CC (2011) Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Mol Biol Cell 22(20):3812–3825
Hill JK, Brett CL, Chyou A, Kallay LM, Sakaguchi M, Rao R, Gillespie PG (2006) Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9. J Neurosci 26(39):9944–9955
Hofstetter W, Siegrist M, Simonin A, Bonny O, Fuster DG (2010) Sodium/hydrogen exchanger NHA2 in osteoclasts: subcellular localization and role in vitro and in vivo. Bone 47(2):331–340
Hoogerwerf WA, Tsao SC, Devuyst O, Levine SA, Yun CH, Yip JW, Cohen ME, Wilson PD, Lazenby AJ, Tse CM, Donowitz M (1996) NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. Am J Physiol 270(1 Pt 1):G29–41
Hu MC, Di Sole F, Zhang J, McLeroy P, Moe OW (2013) Chronic regulation of the renal Na(+)/H(+) exchanger NHE3 by dopamine: translational and posttranslational mechanisms. Am J Physiol Renal Physiol 304(9):F1169–1180
Hua P, Xu H, Uno JK, Lipko MA, Dong J, Kiela PR, Ghishan FK (2007) Sp1 and Sp3 mediate NHE2 gene transcription in the intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 293(1):G146–153
Huang X, Morse LR, Xu Y, Zahradka J, Sychrova H, Stashenko P, Fan F, Battaglino RA (2010) Mutational analysis of NHAoc/NHA2 in Saccharomyces cerevisiae. Biochim Biophys Acta 1800:1241–1247
Hunte C, Screpanti E, Venturi M, Rimon A, Padan E, Michel H (2005) Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature 435(7046):1197–1202
Ikuma M, Kashgarian M, Binder HJ, Rajendran VM (1999) Differential regulation of NHE isoforms by sodium depletion in proximal and distal segments of rat colon. Am J Physiol 276(2 Pt 1):G539–549
Kagami T, Chen S, Memar P, Choi M, Foster LJ, Numata M (2008) Identification and biochemical characterization of the SLC9A7 interactome. Mol Membr Biol 25(5):436–447
Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: possible role of Na+-H+ exchange. Am J Physiol 255(3 Pt 2):H608–615
Kimura T, Kaneko Y, Yamada S, Ishihara H, Senda T, Iwamatsu A, Niki I (2008) The GDP-dependent Rab27a effector coronin 3 controls endocytosis of secretory membrane in insulin-secreting cell lines. J Cell Sci 121(Pt 18):3092–3098
Kinsella JL, Aronson PS (1981) Amiloride inhibition of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol 241(4):F374–379
Kintner DB, Su G, Lenart B, Ballard AJ, Meyer JW, Ng LL, Shull GE, Sun D (2004) Increased tolerance to oxygen and glucose deprivation in astrocytes from Na(+)/H(+) exchanger isoform 1 null mice. Am J Physiol Cell Physiol 287(1):C12–21
Klanke CA, Su YR, Callen DF, Wang Z, Meneton P, Baird N, Kandasamy RA, Orlowski J, Otterud BE, Leppert M et al (1995) Molecular cloning and physical and genetic mapping of a novel human Na+/H+ exchanger (NHE5/SLC9A5) to chromosome 16q22.1. Genomics 25(3):615–622
Klein M, Seeger P, Schuricht B, Alper SL, Schwab A (2000) Polarization of Na(+)/H(+) and Cl(-)/HCO (3)(-) exchangers in migrating renal epithelial cells. J Gen Physiol 115(5):599–608
Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R (2013) Functional evaluation of autism-associated mutations in NHE9. Nat Commun 4:2510
Kozachkov L, Padan E (2013) Conformational changes in NhaA Na+/H+ antiporter. Mol Membr Biol 30(1):90–100
Lagana A, Vadnais J, Le PU, Nguyen TN, Laprade R, Nabi IR, Noel J (2000) Regulation of the formation of tumor cell pseudopodia by the Na(+)/H(+) exchanger NHE1. J Cell Sci 113(Pt 20):3649–3662
Lagarde AE, Franchi AJ, Paris S, Pouyssegur JM (1988) Effect of mutations affecting Na+:H+ antiport activity on tumorigenic potential of hamster lung fibroblasts. J Cell Biochem 36(3):249–260
Lawrence SP, Bright NA, Luzio JP, Bowers K (2010) The sodium/proton exchanger NHE8 regulates late endosomal morphology and function. Mol Biol Cell 21(20):3540–3551
Lazdunski M, Frelin C, Vigne P (1985) The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol 17(11):1029–1042
Ledoussal C, Lorenz JN, Nieman ML, Soleimani M, Schultheis PJ, Shull GE (2001) Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2. Am J Physiol Renal Physiol 281(4):F718–727
Ledoussal C, Woo AL, Miller ML, Shull GE (2001) Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. Am J Physiol Gastrointest Liver Physiol 281(6):G1385–1396
Lee C, Kang HJ, von Ballmoos C, Newstead S, Uzdavinys P, Dotson DL, Iwata S, Beckstein O, Cameron AD, Drew D (2013) A two-domain elevator mechanism for sodium/proton antiport. Nature 501(7468):573–577
Lee SH, Kim T, Park ES, Yang S, Jeong D, Choi Y, Rho J (2008) NHE10, an osteoclast-specific member of the Na+/H+ exchanger family, regulates osteoclast differentiation and survival [corrected]. Biochem Biophys Res Commun 369(2):320–326
Lee BL, Sykes BD, Fliegel L (2013) Structural and functional insights into the cardiac Na(+)/H(+) exchanger. J Mol Cell Cardiol 61:60–67
Li HC, Du Z, Barone S, Rubera I, McDonough AA, Tauc M, Zahedi K, Wang T, Soleimani M (2013) Proximal tubule specific knockout of the Na(+)/H(+) exchanger NHE3: effects on bicarbonate absorption and ammonium excretion. J Mol Med (Berl) 91(8):951–963
Lin PJ, Williams WP, Luu Y, Molday RS, Orlowski J, Numata M (2005) Secretory carrier membrane proteins interact and regulate trafficking of the organellar (Na+, K+)/H+ exchanger NHE7. J Cell Sci 118(Pt 9):1885–1897
Liu L, Schlesinger PH, Slack NM, Friedman PA, Blair HC (2011) High capacity Na+/H+ exchange activity in mineralizing osteoblasts. J Cell Physiol 226(6):1702–1712
Liu C, Xu H, Zhang B, Johansson ME, Li J, Hansson GC, Ghishan FK (2013) NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion. Am J Physiol Cell Physiol 305(1):C121–128
Lorenz JN, Dostanic-Larson I, Shull GE, Lingrel JB (2006) Ouabain inhibits tubuloglomerular feedback in mutant mice with ouabain-sensitive alpha1 Na, K-ATPase. J Am Soc Nephrol 17(9):2457–2463
Lucioni A, Womack C, Musch MW, Rocha FL, Bookstein C, Chang EB (2002) Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function. Am J Physiol Gastrointest Liver Physiol 283(1):G51–56
Lukashova V, Szabo EZ, Jinadasa T, Mokhov A, Litchfield DW, Orlowski J (2011) CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis. J Biol Chem 286(13):11456–11468
Luo J, Chen H, Kintner DB, Shull GE, Sun D (2005) Decreased neuronal death in Na+/H+ exchanger isoform 1-null mice after in vitro and in vivo ischemia. J Neurosci 25(49):11256–11268
Luo J, Chen H, Kintner DB, Shull GE, Sun D (2006) Inhibition of Na+/H+ exchanger isoform 1 attenuates mitochondrial cytochrome C release in cortical neurons following in vitro ischemia. Acta Neurochir Suppl 96:244–248
MacDonald PE, Eliasson L, Rorsman P (2005) Calcium increases endocytotic vesicle size and accelerates membrane fission in insulin-secreting INS-1 cells. J Cell Sci 118(Pt 24):5911–5920
Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti G (1988) Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 318(3):146–150
Markunas CA, Quinn KS, Collins AL, Garrett ME, Lachiewicz AM, Sommer JL, Morrissey-Kane E, Kollins SH, Anastopoulos AD, Ashley-Koch AE (2010) Genetic variants in SLC9A9 are associated with measures of attention-deficit/hyperactivity disorder symptoms in families. Psychiatr Genet 20(2):73–81
Masereel B, Pochet L, Laeckmann D (2003) An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem 38(6):547–554
Miller ML, Andringa A, Schultheis PJ, Shull GE (2011) Loss of the NHE2 Na+/H+ exchanger in mice results in dilation of folliculo-stellate cell canaliculi. J Biomed Biotechnol 2011:510827
Min L, Leung YM, Tomas A, Watson RT, Gaisano HY, Halban PA, Pessin JE, Hou JC (2007) Dynamin is functionally coupled to insulin granule exocytosis. J Biol Chem 282(46):33530–33536
Mitchell P, Moyle J (1965) Stoichiometry of proton translocation through the respiratory chain and adenosine triphosphatase systems of rat liver mitochondria. Nature 208(6):147–151
Moeser AJ, Nighot PK, Ryan KA, Simpson JE, Clarke LL, Blikslager AT (2008) Mice lacking the Na+/H+ exchanger 2 have impaired recovery of intestinal barrier function. Am J Physiol Gastrointest Liver Physiol 295(4):G791–797
Moeser AJ, Nighot PK, Ryan KA, Wooten JG, Blikslager AT (2006) Prostaglandin-mediated inhibition of Na+/H+ exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine. Am J Physiol Gastrointest Liver Physiol 291(5):G885–894
Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321(5886):218–223
Muller T, Wijmenga C, Phillips AD, Janecke A, Houwen RH, Fischer H, Ellemunter H, Fruhwirth M, Offner F, Hofer S, Muller W, Booth IW, Heinz-Erian P (2000) Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 119(6):1506–1513
Murer H, Hopfer U, Kinne R (1976) Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochem J 154(3):597–604
Murtazina R, Kovbasnjuk O, Chen TE, Zachos NC, Chen Y, Kocinsky HS, Hogema BM, Seidler U, de Jonge HR, Donowitz M (2011) NHERF2 is necessary for basal activity, second messenger inhibition, and LPA stimulation of NHE3 in mouse distal ileum. Am J Physiol Cell Physiol 301(1):C126–136
Nakamura S, Amlal H, Schultheis PJ, Galla JH, Shull GE, Soleimani M (1999) HCO-3 reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response. Am J Physiol 276(6 Pt 2):F914–921
Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S (2008) Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res 103(8):891–899
Nakamura N, Tanaka S, Teko Y, Mitsui K, Kanazawa H (2005) Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem 280(2):1561–1572
Nguyen MT, Lee DH, Delpire E, McDonough AA (2013) Differential regulation of Na+ transporters along nephron during ANG II-dependent hypertension: distal stimulation counteracted by proximal inhibition. Am J Physiol Renal Physiol 305(4):F510–519
Nguyen HV, Shull GE, Melvin JE (2000) Muscarinic receptor-induced acidification in sublingual mucous acinar cells: loss of pH recovery in Na+-H+ exchanger-1 deficient mice. J Physiol 523(Pt 1):139–146
Noonan WT, Woo AL, Nieman ML, Prasad V, Schultheis PJ, Shull GE, Lorenz JN (2005) Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine. Am J Physiol Regul Integr Comp Physiol 288(3):R685–691
Numata M, Orlowski J (2001) Molecular cloning and characterization of a novel (Na+, K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem 276(20):17387–17394
Ohgaki R, Fukura N, Matsushita M, Mitsui K, Kanazawa H (2007) Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with the receptor for activated C-kinase 1. J Biol Chem 283:4417–4429
Ohgaki R, Fukura N, Matsushita M, Mitsui K, Kanazawa H (2008) Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1. J Biol Chem 283(7):4417–4429
Ohgaki R, Matsushita M, Kanazawa H, Ogihara S, Hoekstra D, van Ijzendoorn SC (2010) The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells. Mol Biol Cell 21(7):1293–1304
Ohgaki R, Van ISC, Matsushita M, Hoekstra D, Kanazawa H (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry 50(4):443–450
Onishi I, Lin PJ, Diering GH, Williams WP, Numata M (2007) RACK1 associates with NHE5 in focal adhesions and positively regulates the transporter activity. Cell Signal 19(1):194–203
Onishi I, Lin PJ, Numata Y, Austin P, Cipollone J, Roberge M, Roskelley CD, Numata M (2012) Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells. Oncol Rep 27(2):311–317
Orci L, Malaisse-Lagae F, Ravazzola M, Amherdt M, Renold AE (1973) Exocytosis-endocytosis coupling in the pancreatic beta cell. Science 181(4099):561–562
Orlowski J (1993) Heterologous expression and functional properties of amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the rat Na/H exchanger. J Biol Chem 268(22):16369–16377
Orlowski J, Grinstein S (2004) Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch 447(5):549–565
Orlowski J, Kandasamy RA, Shull GE (1992) Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem 267(13):9331–9339
Ouyang Q, Lizarraga SB, Schmidt M, Yang U, Gong J, Ellisor D, Kauer JA, Morrow EM (2013) Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron 80: 97–112
Pan W, Borovac J, Spicer Z, Hoenderop JG, Bindels RJ, Shull GE, Doschak MR, Cordat E, Alexander RT (2012) The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re)absorption. Am J Physiol Renal Physiol 302(8):F943–956
Park K, Evans RL, Watson GE, Nehrke K, Richardson L, Bell SM, Schultheis PJ, Hand AR, Shull GE, Melvin JE (2001) Defective fluid secretion and NaCl absorption in the parotid glands of Na+/H+ exchanger-deficient mice. J Biol Chem 276(29):27042–27050
Peti-Peterdi J, Chambrey R, Bebok Z, Biemesderfer D, St John PL, Abrahamson DR, Warnock DG, Bell PD (2000) Macula densa Na(+)/H(+) exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms. Am J Physiol Renal Physiol 278(3):F452–463
Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A (1999) Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol 276(2 Pt 2):H709–717
Pham L, Purcell P, Morse L, Stashenko P, Battaglino RA (2007) Expression analysis of nha-oc/NHA2: a novel gene selectively expressed in osteoclasts. Gene Expr Patterns 7(8):846–851
Pizzonia JH, Biemesderfer D, Abu-Alfa AK, Wu MS, Exner M, Isenring P, Igarashi P, Aronson PS (1998) Immunochemical characterization of Na+/H+ exchanger isoform NHE4. Am J Physiol 275(4 Pt 2):F510–517
Pouyssegur J, Chambard JC, Franchi A, Paris S, Van Obberghen-Schilling E (1982) Growth factor activation of an amiloride-sensitive Na+/H+ exchange system in quiescent fibroblasts: coupling to ribosomal protein S6 phosphorylation. Proc Natl Acad Sci U S A 79(13):3935–3939
Pulakat L, Cooper S, Knowle D, Mandavia C, Bruhl S, Hetrick M, Gavini N (2005) Ligand-dependent complex formation between the Angiotensin II receptor subtype AT2 and Na+/H + exchanger NHE6 in mammalian cells. Peptides 26(5):863–873
Repishti M, Hogan DL, Pratha V, Davydova L, Donowitz M, Tse CM, Isenberg JI (2001) Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement. Am J Physiol Gastrointest Liver Physiol 281(1):G159–163
Reshkin SJ, Bellizzi A, Albarani V, Guerra L, Tommasino M, Paradiso A, Casavola V (2000) Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na(+)/H(+) exchange, motility, and invasion induced by serum deprivation. J Biol Chem 275(8):5361–5369
Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, Alunni-Fabbroni M, Casavola V, Tommasino M (2000) Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. Faseb J 14(14):2185–2197
Reshkin SJ, Bellizzi A, Cardone RA, Tommasino M, Casavola V, Paradiso A (2003) Paclitaxel induces apoptosis via protein kinase A- and p38 mitogen-activated protein-dependent inhibition of the Na+/H+ exchanger (NHE) NHE isoform 1 in human breast cancer cells. Clin Cancer Res 9(6):2366–2373
Rich IN, Worthington-White D, Garden OA, Musk P (2000) Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood 95(4):1427–1434
Rievaj J, Pan W, Cordat E, Todd Alexander R (2013) The Na+/H+ exchanger isoform 3 is required for active paracellular and transcellular Ca2+ transport across murine cecum. Am J Physiol Gastrointest Liver Physiol 305(4):G303–313
Rocha F, Musch MW, Lishanskiy L, Bookstein C, Sugi K, Xie Y, Chang EB (2001) IFN-gamma downregulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells. Am J Physiol Cell Physiol 280(5):C1224–1232
Rockwell NC, Fuller RS (2002) Specific modulation of Kex2/furin family proteases by potassium. J Biol Chem 277(20):17531–17537
Roxrud I, Raiborg C, Gilfillan GD, Stromme P, Stenmark H (2009) Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease. Exp Cell Res 315(17):3014–3027
Sardet C, Franchi A, Pouyssegur J (1989) Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell 56(2):271–280
Sarker R, Valkhoff VE, Zachos NC, Lin R, Cha B, Chen TE, Guggino S, Zizak M, de Jonge H, Hogema B, Donowitz M (2011) NHERF1 and NHERF2 are necessary for multiple but usually separate aspects of basal and acute regulation of NHE3 activity. Am J Physiol Cell Physiol 300(4):C771–782
Schneider L, Stock CM, Dieterich P, Jensen BH, Pedersen LB, Satir P, Schwab A, Christensen ST, Pedersen SF (2009) The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-alpha in the primary cilium. J Cell Biol 185(1):163–176
Schultheis PJ, Clarke LL, Meneton P, Harline M, Boivin GP, Stemmermann G, Duffy JJ, Doetschman T, Miller ML, Shull GE (1998) Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest 101(6):1243–1253
Schultheis PJ, Clarke LL, Meneton P, Miller ML, Soleimani M, Gawenis LR, Riddle TM, Duffy JJ, Doetschman T, Wang T, Giebisch G, Aronson PS, Lorenz JN, Shull GE (1998) Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H + exchanger. Nat Genet 19(3):282–285
Schwede M, Garbett K, Mirnics K, Geschwind DH, Morrow EM (2013) Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol Psychiatry. DOI: 10.1038/mp.2013.28
Simonin A, Fuster D (2010) Nedd4-1 and beta-arrestin-1 are key regulators of Na+/H+ exchanger 1 ubiquitylation, endocytosis, and function. J Biol Chem 285(49):38293–38303
Spacey SD, Szczygielski BI, McRory JE, Wali GM, Wood NW, Snutch TP (2002) Mutation analysis of the sodium/hydrogen exchanger gene (NHE5) in familial paroxysmal kinesigenic dyskinesia. J Neural Transm 109(9):1189–1194
Steinberg BE, Huynh KK, Brodovitch A, Jabs S, Stauber T, Jentsch TJ, Grinstein S (2010) A cation counterflux supports lysosomal acidification. J Cell Biol 189(7):1171–1186
Stock C, Cardone RA, Busco G, Krahling H, Schwab A, Reshkin SJ (2008) Protons extruded by NHE1: digestive or glue? Eur J Cell Biol 87(8–9):591–599
Stromme P, Dobrenis K, Sillitoe RV, Gulinello M, Ali NF, Davidson C, Micsenyi MC, Stephney G, Ellevog L, Klungland A, Walkley SU (2011) X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 134(Pt 11):3369–3383
Sullivan S, Alex P, Dassopoulos T, Zachos NC, Iacobuzio-Donahue C, Donowitz M, Brant SR, Cuffari C, Harris ML, Datta LW, Conklin L, Chen Y, Li X (2009) Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea. Inflamm Bowel Dis 15(2):261–274
Szabo EZ, Numata M, Lukashova V, Iannuzzi P, Orlowski J (2005) beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform. Proc Natl Acad Sci USA 102(8):2790–2795
Szabo EZ, Numata M, Shull GE, Orlowski J (2000) Kinetic and pharmacological properties of human brain Na(+)/H(+) exchanger isoform 5 stably expressed in Chinese hamster ovary cells. J Biol Chem 275(9):6302–6307
Szaszi K, Paulsen A, Szabo EZ, Numata M, Grinstein S, Orlowski J (2002) Clathrin-mediated endocytosis and recycling of the neuron-specific Na+/H+ exchanger NHE5 isoform. Regulation by phosphatidylinositol 3′-kinase and the actin cytoskeleton. J Biol Chem 277(45):42623–42632
Takahashi Y, Hosoki K, Matsushita M, Funatsuka M, Saito K, Kanazawa H, Goto Y, Saitoh S (2011) A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. Am J Med Genet B Neuropsychiatr Genet 156B(7):799–807
Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A (2000) Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation 102(25):3032–3038
Tse CM, Brant SR, Walker MS, Pouyssegur J, Donowitz M (1992) Cloning and sequencing of a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). J Biol Chem 267(13):9340–9346
Tse CM, Levine SA, Yun CH, Khurana S, Donowitz M (1994) Na+/H+ exchanger-2 is an O-linked but not an N-linked sialoglycoprotein. Biochemistry 33(44):12954–12961
Tse CM, Levine SA, Yun CH, Montrose MH, Little PJ, Pouyssegur J, Donowitz M (1993) Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H+ exchanger isoform (NHE-2). J Biol Chem 268(16):11917–11924
Villa-Abrille MC, Cingolani E, Cingolani HE, Alvarez BV (2011) Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol 300(4):H1237–1251
Wang E, Brown PS, Aroeti B, Chapin SJ, Mostov KE, Dunn KW (2000) Apical and basolateral endocytic pathways of MDCK cells meet in acidic common endosomes distinct from a nearly-neutral apical recycling endosome. Traffic 1(6):480–493
Wang D, Hu J, Bobulescu IA, Quill TA, McLeroy P, Moe OW, Garbers DL (2007) A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc Natl Acad Sci U S A 104(22):9325–9330
Wang D, King SM, Quill TA, Doolittle LK, Garbers DL (2003) A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility. Nat Cell Biol 5(12):1117–1122
Wang Z, Orlowski J, Shull GE (1993) Primary structure and functional expression of a novel gastrointestinal isoform of the rat Na/H exchanger. J Biol Chem 268(16):11925–11928
Wang T, Yang CL, Abbiati T, Schultheis PJ, Shull GE, Giebisch G, Aronson PS (1999) Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Physiol 277(2 Pt 2):F298–302
White RL, Doeller JE, Verselis VK, Wittenberg BA (1990) Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++. J Gen Physiol 95(6):1061–1075
Wieczorek H, Brown D, Grinstein S, Ehrenfeld J, Harvey WR (1999) Animal plasma membrane energization by proton-motive V-ATPases. Bioessays 21(8):637–648
Woo AL, Noonan WT, Schultheis PJ, Neumann JC, Manning PA, Lorenz JN, Shull GE (2003) Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect. Am J Physiol Renal Physiol 284(6):F1190–1198
Xia Y, Zhao P, Xue J, Gu XQ, Sun X, Yao H, Haddad GG (2003) Na+ channel expression and neuronal function in the Na+/H+ exchanger 1 null mutant mouse. J Neurophysiol 89(1):229–236
Xiang M, Feng M, Muend S, Rao R (2007) A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension. Proc Natl Acad Sci USA 104(47):18677–18681
Xinhan L, Matsushita M, Numaza M, Taguchi A, Mitsui K, Kanazawa H (2011) Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. Am J Physiol Cell Physiol 301(6):C1431–1444
Xu H, Chen H, Dong J, Lynch R, Ghishan FK (2008) Gastrointestinal distribution and kinetic characterization of the sodium-hydrogen exchanger isoform 8 (NHE8). Cell Physiol Biochem 21(1–3):109–116
Xu H, Li J, Chen H, Wang C, Ghishan FK (2013) NHE8 plays important roles in gastric mucosal protection. Am J Physiol Gastrointest Liver Physiol 304(3):G257–261
Xu L, Mann G, Meissner G (1996) Regulation of cardiac Ca2+ release channel (ryanodine receptor) by Ca2+, H+, Mg2+, and adenine nucleotides under normal and simulated ischemic conditions. Circ Res 79(6):1100–1109
Xu H, Zhang B, Li J, Wang C, Chen H, Ghishan FK (2012) Impaired mucin synthesis and bicarbonate secretion in the colon of NHE8 knockout mice. Am J Physiol Gastrointest Liver Physiol 303(3):G335–343
Yang J, Singh V, Cha B, Chen TE, Sarker R, Murtazina R, Jin S, Zachos NC, Patterson GH, Tse CM, Kovbasnjuk O, Li X, Donowitz M (2013) NHERF2 protein mobility rate is determined by a unique C-terminal domain that is also necessary for its regulation of NHE3 protein in OK cells. J Biol Chem 288(23):16960–16974
Yao H, Ma E, Gu XQ, Haddad GG (1999) Intracellular pH regulation of CA1 neurons in Na(+)/H(+) isoform 1 mutant mice. J Clin Invest 104(5):637–645
Ye G, Chen C, Han D, Xiong X, Kong Y, Wan B, Yu L (2006) Cloning of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene expressed specifically in testis. Mol Biol Rep 33(3):175–180
Yeruva S, Farkas K, Hubricht J, Rode K, Riederer B, Bachmann O, Cinar A, Rakonczay Z, Molnar T, Nagy F, Wedemeyer J, Manns M, Raddatz D, Musch MW, Chang EB, Hegyi P, Seidler U (2010) Preserved Na(+)/H(+) exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis. Inflamm Bowel Dis 16(7):1149–1161
Zeymer U, Suryapranata H, Monassier JP, Opolski G, Davies J, Rasmanis G, Linssen G, Tebbe U, Schroder R, Tiemann R, Machnig T, Neuhaus KL (2001) The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial. J Am Coll Cardiol 38(6):1644–1650
Zhang J, Bobulescu IA, Goyal S, Aronson PS, Baum MG, Moe OW (2007) Characterization of Na+/H+ exchanger NHE8 in cultured renal epithelial cells. Am J Physiol Renal Physiol 293(3):F761–766
Zhang-James Y, DasBanerjee T, Sagvolden T, Middleton FA, Faraone SV (2011) SLC9A9 mutations, gene expression, and protein–protein interactions in rat models of attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 156B(7):835–843
Acknowledgments
We apologize to the many investigators whose work we could not reference due to space limitations. D.F. was supported by a Swiss National Science Foundation grant (# 3100A0-117732), the Swiss National Centre of Competence in Research (NCCR TransCure and NCCR kidney.ch), the Novartis Research Foundation, and by a Medical Research Position Award of the Foundation Prof. Dr. Max Cloëtta. R.T.A is supported by operating funds from the Kidney Foundation of Canada and the Canadian Institute for Health Research (CIHR) as well as a Clinician Scientist Award from CIHR and a Clinical Investigator Award from Alberta Innovates Health Solutions.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published as part of the Special Issue “Sodium-dependent transporters in health and disease.”
Rights and permissions
About this article
Cite this article
Fuster, D.G., Alexander, R.T. Traditional and emerging roles for the SLC9 Na+/H+ exchangers. Pflugers Arch - Eur J Physiol 466, 61–76 (2014). https://doi.org/10.1007/s00424-013-1408-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-013-1408-8