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Traditional and emerging roles for the SLC9 Na+/H+ exchangers

  • Daniel G. FusterEmail author
  • R. Todd Alexander
Invited Review

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.

Keywords

Sodium/hydrogen exchanger NHE SLC9 

Notes

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.

References

  1. 1.
    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):679–691PubMedGoogle Scholar
  2. 2.
    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):C887–896PubMedGoogle Scholar
  3. 3.
    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):C412–418PubMedGoogle Scholar
  4. 4.
    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):C1146–1157PubMedGoogle Scholar
  5. 5.
    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):4383–4388PubMedGoogle Scholar
  6. 6.
    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):G125–133PubMedGoogle Scholar
  7. 7.
    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):4377–4382PubMedGoogle Scholar
  8. 8.
    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):F364–370PubMedGoogle Scholar
  9. 9.
    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):452–459PubMedGoogle Scholar
  10. 10.
    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: 180–192Google Scholar
  11. 11.
    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):180–192PubMedCentralPubMedGoogle Scholar
  12. 12.
    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):F1495–1502PubMedGoogle Scholar
  13. 13.
    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):C844–850PubMedGoogle Scholar
  14. 14.
    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):F255–261PubMedGoogle Scholar
  15. 15.
    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):C788–795PubMedGoogle Scholar
  16. 16.
    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):F833–840PubMedGoogle Scholar
  17. 17.
    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):F289–299PubMedGoogle Scholar
  18. 18.
    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):485–494PubMedCentralPubMedGoogle Scholar
  19. 19.
    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):C1629–1638PubMedGoogle Scholar
  20. 20.
    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):1895–1904PubMedCentralPubMedGoogle Scholar
  21. 21.
    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):420–427PubMedGoogle Scholar
  22. 22.
    Brett CL, Donowitz M, Rao R (2005) Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 288(2):C223–239PubMedGoogle Scholar
  23. 23.
    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):772–776PubMedGoogle Scholar
  24. 24.
    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):S41–49PubMedGoogle Scholar
  25. 25.
    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):786–795PubMedGoogle Scholar
  26. 26.
    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):C90–98PubMedGoogle Scholar
  27. 27.
    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):F707–717PubMedGoogle Scholar
  28. 28.
    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):F379–386PubMedGoogle Scholar
  29. 29.
    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):902–912PubMedCentralPubMedGoogle Scholar
  30. 30.
    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):5049–5063PubMedGoogle Scholar
  31. 31.
    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):759–766PubMedGoogle Scholar
  32. 32.
    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):57–66PubMedGoogle Scholar
  33. 33.
    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):10463–10469PubMedGoogle Scholar
  34. 34.
    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):139–148PubMedGoogle Scholar
  35. 35.
    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):2035–2043PubMedGoogle Scholar
  36. 36.
    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):2612–2619PubMedGoogle Scholar
  37. 37.
    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):733–740PubMedGoogle Scholar
  38. 38.
    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):10004–10009PubMedCentralPubMedGoogle Scholar
  39. 39.
    Demaurex N (2002) pH Homeostasis of cellular organelles. News Physiol Sci 17:1–5PubMedGoogle Scholar
  40. 40.
    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):1087–1096PubMedGoogle Scholar
  41. 41.
    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):1425–1436PubMedGoogle Scholar
  42. 42.
    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):13892–13903PubMedGoogle Scholar
  43. 43.
    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):2246–2257PubMedCentralPubMedGoogle Scholar
  44. 44.
    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: 3435–3448Google Scholar
  45. 45.
    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):R1659–1669PubMedGoogle Scholar
  46. 46.
    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):236–251PubMedCentralPubMedGoogle Scholar
  47. 47.
    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):84–93PubMedGoogle Scholar
  48. 48.
    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):1547–1556PubMedGoogle Scholar
  49. 49.
    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):1391–1402PubMedGoogle Scholar
  50. 50.
    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):12781–12789PubMedGoogle Scholar
  51. 51.
    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):G776–784PubMedGoogle Scholar
  52. 52.
    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):1003–1010PubMedCentralPubMedGoogle Scholar
  53. 53.
    Goyal S, Mentone S, Aronson PS (2005) Immunolocalization of NHE8 in rat kidney. Am J Physiol Renal Physiol 288(3):F530–538PubMedGoogle Scholar
  54. 54.
    Goyal S, Vanden Heuvel G, Aronson PS (2003) Renal expression of novel Na+/H+ exchanger isoform NHE8. Am J Physiol Renal Physiol 284(3):F467–473PubMedGoogle Scholar
  55. 55.
    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):5209–5218PubMedGoogle Scholar
  56. 56.
    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):C496–503PubMedGoogle Scholar
  57. 57.
    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):G689–699PubMedGoogle Scholar
  58. 58.
    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):2625–2639PubMedGoogle Scholar
  59. 59.
    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):F937–944PubMedCentralPubMedGoogle Scholar
  60. 60.
    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):G348–356PubMedGoogle Scholar
  61. 61.
    Haworth RS, Frohlich O, Fliegel L (1993) Multiple carbohydrate moieties on the Na+/H+ exchanger. Biochem J 289(Pt 3):637–640PubMedGoogle Scholar
  62. 62.
    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):31676–31684PubMedGoogle Scholar
  63. 63.
    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):C526–534PubMedGoogle Scholar
  64. 64.
    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):3812–3825PubMedCentralPubMedGoogle Scholar
  65. 65.
    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):9944–9955PubMedGoogle Scholar
  66. 66.
    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):331–340PubMedGoogle Scholar
  67. 67.
    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):G29–41PubMedGoogle Scholar
  68. 68.
    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):F1169–1180PubMedGoogle Scholar
  69. 69.
    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):G146–153PubMedGoogle Scholar
  70. 70.
    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 1800:1241–1247Google Scholar
  71. 71.
    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):1197–1202PubMedGoogle Scholar
  72. 72.
    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):G539–549PubMedGoogle Scholar
  73. 73.
    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):436–447PubMedGoogle Scholar
  74. 74.
    Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: possible role of Na+-H+ exchange. Am J Physiol 255(3 Pt 2):H608–615PubMedGoogle Scholar
  75. 75.
    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):3092–3098PubMedGoogle Scholar
  76. 76.
    Kinsella JL, Aronson PS (1981) Amiloride inhibition of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol 241(4):F374–379PubMedGoogle Scholar
  77. 77.
    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):C12–21PubMedGoogle Scholar
  78. 78.
    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):615–622PubMedGoogle Scholar
  79. 79.
    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):599–608PubMedCentralPubMedGoogle Scholar
  80. 80.
    Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R (2013) Functional evaluation of autism-associated mutations in NHE9. Nat Commun 4:2510PubMedGoogle Scholar
  81. 81.
    Kozachkov L, Padan E (2013) Conformational changes in NhaA Na+/H+ antiporter. Mol Membr Biol 30(1):90–100PubMedGoogle Scholar
  82. 82.
    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):3649–3662PubMedGoogle Scholar
  83. 83.
    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):249–260PubMedGoogle Scholar
  84. 84.
    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):3540–3551PubMedCentralPubMedGoogle Scholar
  85. 85.
    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):1029–1042PubMedGoogle Scholar
  86. 86.
    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):F718–727PubMedGoogle Scholar
  87. 87.
    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):G1385–1396PubMedGoogle Scholar
  88. 88.
    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):573–577PubMedGoogle Scholar
  89. 89.
    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):320–326PubMedGoogle Scholar
  90. 90.
    Lee BL, Sykes BD, Fliegel L (2013) Structural and functional insights into the cardiac Na(+)/H(+) exchanger. J Mol Cell Cardiol 61:60–67PubMedGoogle Scholar
  91. 91.
    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):951–963Google Scholar
  92. 92.
    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):1885–1897PubMedGoogle Scholar
  93. 93.
    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):1702–1712PubMedGoogle Scholar
  94. 94.
    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):C121–128PubMedGoogle Scholar
  95. 95.
    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):2457–2463PubMedGoogle Scholar
  96. 96.
    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):G51–56PubMedGoogle Scholar
  97. 97.
    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):11456–11468PubMedGoogle Scholar
  98. 98.
    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):11256–11268PubMedGoogle Scholar
  99. 99.
    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 96:244–248PubMedGoogle Scholar
  100. 100.
    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):5911–5920PubMedGoogle Scholar
  101. 101.
    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):146–150PubMedGoogle Scholar
  102. 102.
    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):73–81PubMedCentralPubMedGoogle Scholar
  103. 103.
    Masereel B, Pochet L, Laeckmann D (2003) An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem 38(6):547–554PubMedGoogle Scholar
  104. 104.
    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 2011:510827PubMedCentralPubMedGoogle Scholar
  105. 105.
    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):33530–33536PubMedGoogle Scholar
  106. 106.
    Mitchell P, Moyle J (1965) Stoichiometry of proton translocation through the respiratory chain and adenosine triphosphatase systems of rat liver mitochondria. Nature 208(6):147–151PubMedGoogle Scholar
  107. 107.
    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):G791–797PubMedGoogle Scholar
  108. 108.
    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):G885–894PubMedGoogle Scholar
  109. 109.
    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):218–223PubMedCentralPubMedGoogle Scholar
  110. 110.
    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):1506–1513PubMedGoogle Scholar
  111. 111.
    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):597–604PubMedGoogle Scholar
  112. 112.
    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):C126–136PubMedGoogle Scholar
  113. 113.
    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):F914–921PubMedGoogle Scholar
  114. 114.
    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):891–899PubMedGoogle Scholar
  115. 115.
    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):1561–1572PubMedGoogle Scholar
  116. 116.
    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):F510–519PubMedGoogle Scholar
  117. 117.
    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):139–146PubMedGoogle Scholar
  118. 118.
    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):R685–691PubMedGoogle Scholar
  119. 119.
    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):17387–17394PubMedGoogle Scholar
  120. 120.
    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 283:4417–4429Google Scholar
  121. 121.
    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):4417–4429PubMedGoogle Scholar
  122. 122.
    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):1293–1304PubMedCentralPubMedGoogle Scholar
  123. 123.
    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):443–450PubMedGoogle Scholar
  124. 124.
    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):194–203PubMedGoogle Scholar
  125. 125.
    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):311–317PubMedGoogle Scholar
  126. 126.
    Orci L, Malaisse-Lagae F, Ravazzola M, Amherdt M, Renold AE (1973) Exocytosis-endocytosis coupling in the pancreatic beta cell. Science 181(4099):561–562PubMedGoogle Scholar
  127. 127.
    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):16369–16377PubMedGoogle Scholar
  128. 128.
    Orlowski J, Grinstein S (2004) Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch 447(5):549–565PubMedGoogle Scholar
  129. 129.
    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):9331–9339PubMedGoogle Scholar
  130. 130.
    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: 97–112Google Scholar
  131. 131.
    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):F943–956PubMedGoogle Scholar
  132. 132.
    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):27042–27050PubMedGoogle Scholar
  133. 133.
    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):F452–463PubMedGoogle Scholar
  134. 134.
    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):H709–717PubMedGoogle Scholar
  135. 135.
    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):846–851PubMedCentralPubMedGoogle Scholar
  136. 136.
    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):F510–517PubMedGoogle Scholar
  137. 137.
    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):3935–3939PubMedCentralPubMedGoogle Scholar
  138. 138.
    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):863–873PubMedGoogle Scholar
  139. 139.
    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):G159–163PubMedGoogle Scholar
  140. 140.
    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):5361–5369PubMedGoogle Scholar
  141. 141.
    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):2185–2197PubMedGoogle Scholar
  142. 142.
    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):2366–2373PubMedGoogle Scholar
  143. 143.
    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):1427–1434PubMedGoogle Scholar
  144. 144.
    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):G303–313PubMedGoogle Scholar
  145. 145.
    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):C1224–1232PubMedGoogle Scholar
  146. 146.
    Rockwell NC, Fuller RS (2002) Specific modulation of Kex2/furin family proteases by potassium. J Biol Chem 277(20):17531–17537PubMedGoogle Scholar
  147. 147.
    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):3014–3027PubMedGoogle Scholar
  148. 148.
    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):271–280PubMedGoogle Scholar
  149. 149.
    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):C771–782PubMedGoogle Scholar
  150. 150.
    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):163–176PubMedGoogle Scholar
  151. 151.
    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):1243–1253PubMedCentralPubMedGoogle Scholar
  152. 152.
    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):282–285PubMedGoogle Scholar
  153. 153.
    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.2013.28Google Scholar
  154. 154.
    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):38293–38303PubMedGoogle Scholar
  155. 155.
    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):1189–1194PubMedGoogle Scholar
  156. 156.
    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):1171–1186PubMedGoogle Scholar
  157. 157.
    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):591–599PubMedGoogle Scholar
  158. 158.
    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):3369–3383PubMedGoogle Scholar
  159. 159.
    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):261–274PubMedCentralPubMedGoogle Scholar
  160. 160.
    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):2790–2795PubMedGoogle Scholar
  161. 161.
    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):6302–6307PubMedGoogle Scholar
  162. 162.
    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):42623–42632PubMedGoogle Scholar
  163. 163.
    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):799–807PubMedGoogle Scholar
  164. 164.
    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):3032–3038PubMedGoogle Scholar
  165. 165.
    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):9340–9346PubMedGoogle Scholar
  166. 166.
    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):12954–12961PubMedGoogle Scholar
  167. 167.
    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):11917–11924PubMedGoogle Scholar
  168. 168.
    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):H1237–1251PubMedGoogle Scholar
  169. 169.
    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):480–493PubMedGoogle Scholar
  170. 170.
    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):9325–9330PubMedCentralPubMedGoogle Scholar
  171. 171.
    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):1117–1122PubMedGoogle Scholar
  172. 172.
    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):11925–11928PubMedGoogle Scholar
  173. 173.
    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):F298–302PubMedGoogle Scholar
  174. 174.
    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):1061–1075PubMedGoogle Scholar
  175. 175.
    Wieczorek H, Brown D, Grinstein S, Ehrenfeld J, Harvey WR (1999) Animal plasma membrane energization by proton-motive V-ATPases. Bioessays 21(8):637–648PubMedGoogle Scholar
  176. 176.
    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):F1190–1198PubMedGoogle Scholar
  177. 177.
    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):229–236PubMedGoogle Scholar
  178. 178.
    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):18677–18681PubMedGoogle Scholar
  179. 179.
    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):C1431–1444PubMedGoogle Scholar
  180. 180.
    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):109–116PubMedGoogle Scholar
  181. 181.
    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):G257–261PubMedGoogle Scholar
  182. 182.
    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):1100–1109PubMedGoogle Scholar
  183. 183.
    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):G335–343PubMedGoogle Scholar
  184. 184.
    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):16960–16974PubMedGoogle Scholar
  185. 185.
    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):637–645PubMedCentralPubMedGoogle Scholar
  186. 186.
    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):175–180PubMedGoogle Scholar
  187. 187.
    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):1149–1161PubMedGoogle Scholar
  188. 188.
    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):1644–1650PubMedGoogle Scholar
  189. 189.
    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):F761–766PubMedCentralPubMedGoogle Scholar
  190. 190.
    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):835–843PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Division of Nephrology, Hypertension and Clinical Pharmacology and Institute of Biochemistry and Molecular MedicineUniversity of BernBernSwitzerland
  2. 2.Division of Nephrology, Department of Pediatrics, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada

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