Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi

SLC9

Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_101935-1

Synonyms

Historical Background

All living cells are critically dependent on homeostatic mechanisms that regulate intracellular pH, Na+ content, and, as a result, cell volume. Correspondingly, Na+ and H+ are among the most prevalent ions in living cells and are essential in cell bioenergetics. In 1974, West and Mitchell discovered sodium proton antiport activity in bacterial cells and suggested that Na+/H+ antiporter proteins have primary roles in the homeostasis of these cations (West and Mitchell 1974). Since then, sodium proton antiporters have been identified in the cytoplasmic and organelle membranes of almost all cells, including those of plants, animals and microorganisms. Furthermore, increasing numbers of these antiporters are being identified as human drug targets.

The SLC9 gene family encodes Na+/H+exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the...

Keywords

Migration Ischemia Diarrhea Luminal Gall 
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References

  1. Bell SM, Schreiner CM, Schultheis PJ, Miller ML, Evans RL, Vorhees CV, et al. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Phys. 1999;276:C788–95.Google Scholar
  2. Christianson AL, Stevenson RE, van der Meyden CH, Pelser J, Theron FW, van Rensburg PL, et al. 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. 1999;36:759–66.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Donowitz M, Ming Tse C, Fuster D. SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol Asp Med. 2013;34:236–51. doi:10.1016/j.mam.2012.05.001.CrossRefGoogle Scholar
  4. Garbern JY, Neumann M, Trojanowski JQ, Lee VM, Feldman G, Norris JW, et al. A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain. 2010;133:1391–402. doi:10.1093/brain/awq071.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, et al. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet. 2008;82:1003–10. doi:10.1016/j.ajhg.2008.01.013.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Hunte C, Screpanti E, Venturi M, Rimon A, Padan E, Michel H. Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature. 2005;435:1197–202. doi:10.1038/nature03692.CrossRefPubMedGoogle Scholar
  7. Kondapalli KC, Hack A, Schushan M, Landau M, Ben-Tal N, Rao R. Functional evaluation of autism-associated mutations in NHE9. Nat Commun. 2013;4:2510. doi:10.1038/ncomms3510.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Landau M, Herz K, Padan E, Ben-Tal N. Model structure of the Na+/H+ exchanger 1 (NHE1) – functional and clinical implications. J Biol Chem. 2007;282:37854–63. doi:10.1074/jbc.M705460200.CrossRefPubMedGoogle Scholar
  9. Milosavljevic N, Monet M, Lena I, Brau F, Lacas-Gervais S, Feliciangeli S, et al. The intracellular Na(+)/H(+) exchanger NHE7 effects a Na(+)-coupled, but not K(+)-coupled proton-loading mechanism in endocytosis. Cell Rep. 2014;7:689–96. doi:10.1016/j.celrep.2014.03.054.CrossRefPubMedGoogle Scholar
  10. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008;321:218–23. doi:10.1126/science.1157657.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Nygaard EB, Lagerstedt JO, Bjerre G, Shi B, Budamagunta M, Poulsen KA, et al. Structural modeling and electron paramagnetic resonance spectroscopy of the human Na+/H+ exchanger isoform 1, NHE1. J Biol Chem. 2011;286:634–48. doi:10.1074/jbc.M110.159202.CrossRefPubMedGoogle Scholar
  12. Orlowski J, Grinstein S. Na+/H+ exchangers. Compr Physiol. 2011;1:2083–100. doi:10.1002/cphy.c110020.PubMedGoogle Scholar
  13. Padan E, Landau M. Sodium-Proton (Na+/H+) antiporters: properties and roles in health and disease. In: Sigel A, Sigel H, Sigel RKO, editors. The alkali metal ions: their role for life. Cham: Springer International Publishing; 2016. p. 391–458.CrossRefGoogle Scholar
  14. Schwede M, Garbett K, Mirnics K, Geschwind DH, Morrow EM. Genes for endosomal NHE6 and NHE9 are misregulated in autism brains. Mol Psychiatry. 2014;19:277–9. doi:10.1038/mp.2013.28.CrossRefPubMedGoogle Scholar
  15. Slepkov ER, Rainey JK, Li X, Liu Y, Cheng FJ, Lindhout DA, et al. Structural and functional characterization of transmembrane segment IV of the NHE1 isoform of the Na+/H+ exchanger. J Biol Chem. 2005;280:17863–72.CrossRefPubMedGoogle Scholar
  16. Stromme P, Dobrenis K, Sillitoe RV, Gulinello M, Ali NF, Davidson C, et al. X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain. 2011;134:3369–83. doi:10.1093/brain/awr250.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Wakabayashi S, Pang T, Su X, Shigekawa M. A novel topology model of the human Na(+)/H(+) exchanger isoform 1. J Biol Chem. 2000;275:7942–9.CrossRefPubMedGoogle Scholar
  18. Wakabayashi S, Hisamitsu T, Nakamura TY. Regulation of the cardiac Na(+)/H(+) exchanger in health and disease. J Mol Cell Cardiol. 2013;61:68–76. doi:10.1016/j.yjmcc.2013.02.007.CrossRefPubMedGoogle Scholar
  19. West IC, Mitchell P. Proton/sodium ion antiport in Escherichia coli. Biochem J. 1974;144:87–90.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2016

Authors and Affiliations

  1. 1.Department of BiologyTechnion – Israel Institute of TechnologyHaifaIsrael