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Gene Review

SLC9A1  -  solute carrier family 9, subfamily A (NHE1...

Homo sapiens

Synonyms: APNH, APNH1, NHE-1, NHE1, Na(+)/H(+) antiporter, amiloride-sensitive, ...
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Disease relevance of SLC9A1

  • The low-serum component of this microenvironment confers increased motility and invasion in breast cancer cells by activating the Na+/H+ exchanger isoform 1 (NHE1) [1].
  • The NHE1 to NHE3 and NHE5 loci did not demonstrate evidence for linkage to ESRD [2].
  • APNH is a plausible candidate gene for human essential hypertension; the APNH polymorphism combined with a knowledge of its genetic map location allow this candidate to be tested in hypertensive kindreds and sib-pairs [3].
  • In situ hybridization revealed that NHE1 mRNA in the turbinate mucosa and nasal polyp was localized in the epithelial layer and submucosal glands [4].
  • For this study, age-matched type 2 diabetic (n=8) and normal (n=8) pregnant women were recruited to investigate the effects of controlled hyperglycemia on the expression of placental NHE-1 at term delivery [5].

High impact information on SLC9A1

  • Through its effects on pHi homeostasis, cell volume, and the actin cortical network, NHE1 regulates a number of cell behaviors, including adhesion, shape determination, migration, and proliferation [6].
  • Recently, it was determined that NHE1 also functions as a membrane anchor for the actin-based cytoskeleton, independently of its role in ion translocation [6].
  • Here, we show that the plasma membrane ion exchanger NHE1 acts as an anchor for actin filaments to control the integrity of the cortical cytoskeleton [7].
  • Fibroblasts expressing NHE1 with mutations that disrupt ERM binding, but not ion translocation, have impaired organization of focal adhesions and actin stress fibers, and an irregular cell shape [7].
  • NHE1 and ERM proteins associate directly and colocalize in lamellipodia [7].

Chemical compound and disease context of SLC9A1

  • It was hypothesized that the increase in intracellular Na(+) ([Na(+)](i)) mediated by NHE-1 activity may induce the reverse mode of Na(+)/Ca(2+) exchanger (NCX(rev)) increasing intracellular Ca(2+) ([Ca(2+)](i)) which in turn will induce hypertrophy [8].
  • Taken together, our results suggest that CD44 interaction with a ROK-activated NHE1 (a Na(+)-H(+) exchanger) in cholesterol/ganglioside-containing lipid rafts plays a pivotal role in promoting intracellular/extracellular acidification required for Hyal-2 and cysteine proteinase-mediated matrix degradation and breast cancer progression [9].
  • RESULTS: Human ventricular myocytes exhibited readily detectable sarcolemmal NHE activity after the induction of intracellular acidosis, and this activity was suppressed by the NHE1-selective inhibitor HOE-642 (cariporide) at 1 micromol/L [10].
  • Selective insulin resistance and hyperinsulinism estimulates the tubular sodium-hydrogen exchanger and facilitates the active reabsorption of urate [11].
  • During ischemia, there is a metabolic mismatch between glycolysis and glucose oxidation that results in accumulation of hydrogen ions, which, in turn, activates the Na+/H+ exchange system (NHE-1), leading to Na+ and Ca2+ overload and cell death [12].

Biological context of SLC9A1

  • Direct binding of the Na--H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation [7].
  • The phosphorylation state of CHP may therefore be an important signal controlling mitogenic regulation of NHE1 [13].
  • We conclude that NHE1 promotes cell survival by dual mechanisms: by defending cell volume and pH(i) through Na(+)/H(+) exchange and by functioning as a scaffold for recruitment of a signalplex that includes ERM, phosphoinositide 3-kinase, and Akt [14].
  • Apoptosis results in cell shrinkage and intracellular acidification, processes opposed by the ubiquitously expressed NHE1 Na(+)/H(+) exchanger [14].
  • We propose that serum-independent activation of NHE1 by bound CHP2 is one of the key mechanisms for the maintenance of high pH(i) and the resistance to serum deprivation-induced cell death in malignantly transformed cells [15].

Anatomical context of SLC9A1

  • We propose a structural role for NHE1 in regulating the cortical cytoskeleton that is independent of its function as an ion exchanger [7].
  • Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines [1].
  • However, we have found that the Na+/H+ exchanger (NHE), NHE1, is functionally active in these cells, and like AC8 (and AC6) it resides in lipid rafts or caveolae, which may create cellular microdomains where pH(i) is tightly regulated [16].
  • Long-term exposure (24 h) of HT-29 cells to IFN-gamma resulted in a concentration-dependent decrease in NHE1 activity [17].
  • Caco-2 cells express endogenous NHE1, NHE2 and NHE3 proteins, as detected by immunoblotting [18].

Associations of SLC9A1 with chemical compounds

  • Ectopic NHE1, but not NHE3, expression rescued NHE1-null cells from apoptosis induced by staurosporine or N-ethylmaleimide-stimulated KCl efflux [14].
  • Co-precipitation experiments demonstrated the interaction of human TSC with NHE1 in vitro and in vivo, and 45Ca(2+) overlay assay revealed that TSC binds Ca(2+) [19].
  • Furthermore, we found that a novel synthetic aminoguanidine derivative, T-162559 ((5E,7S)-[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylideneamino] guanidine dimethanesulfonate), causes a selective inhibition of hNHE1 with more potent activity than cariporide and eniporide (IC50 value of 0.96 nM) [20].
  • Potent and selective inhibition of the human Na+/H+ exchanger isoform NHE1 by a novel aminoguanidine derivative T-162559 [20].
  • Each residue was mutated to cysteine in cysteine-less NHE1 [21].

Physical interactions of SLC9A1


Enzymatic interactions of SLC9A1

  • These findings indicate that NIK acts downstream of platelet-derived growth factor receptors to phosphorylate and activate NHE1 divergently of its activation of JNK [25].

Regulatory relationships of SLC9A1

  • Transient overexpression of CHP inhibits serum- and GTP-ase-stimulated NHE1 activity [13].
  • Serum (10%) induced a significant cytoplasmic alkalinization (0.1-0.2 pH unit) in cells co-expressing CHP1 and NHE1 but not in cells co-expressing CHP2 and NHE1 [15].
  • Rac1 and RhoA were antagonistic regulators of both basal and stimulated tumour cell NHE1 activity [26].
  • Rapid (<10 min) stimulation of NHE1 with a Ga13/Gaz chimera also was inhibited by a kinase-inactive MEKK [27].
  • In most tissues, it is proposed that the NHE-1 could compensate for an inhibited MCT to prevent acidification, but in melanoma cells this did not occur [28].

Other interactions of SLC9A1

  • These properties of CHP2/NHE1 cells are similar to those of malignantly transformed cells [15].
  • CAII did not bind to acidic sequences in NHE1 that were similar to the CAII binding site of bicarbonate transporters [22].
  • The activity of RhoA and Rac1 was modified using their dominant negative and constitutively active mutants and the activity of NHE1, cell motility/invasion, F-actin content and cell shape were measured [26].
  • We conclude that AE2 operates in parallel with NHE1 to regulate pH(i) during RVD of human cervical cancer cells [29].
  • To date, 5 isoforms of NHE have been cloned in mammals (NHE1 to NHE5) [2].

Analytical, diagnostic and therapeutic context of SLC9A1


  1. Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Cardone, R.A., Bagorda, A., Bellizzi, A., Busco, G., Guerra, L., Paradiso, A., Casavola, V., Zaccolo, M., Reshkin, S.J. Mol. Biol. Cell (2005) [Pubmed]
  2. Human Na+/H+ exchanger genes : identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. Yu, H., Freedman, B.I., Rich, S.S., Bowden, D.W. Hypertension (2000) [Pubmed]
  3. The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1. Dudley, C.R., Giuffra, L.A., Tippett, P., Kidd, K.K., Reeders, S.T. Hum. Genet. (1990) [Pubmed]
  4. Expression of mRNA transcripts of the Na+/H+ and Cl-/HCO3- exchanger isoforms in human nasal mucosa. Lee, S.H., Seok, Y.S., Jung, H.H., Oh, B.H., Lee, H.M., Kwon, S.Y., Jung, K.Y. Acta Otolaryngol. (2002) [Pubmed]
  5. Suppression of Na+-H+ exchanger-1 in placentas of type 2 diabetic pregnant women: possible functional implication. Khan, I., Al-Awadi, F.M., Nandakumaran, M., Abul, H., Al-Azemi, M. Acta diabetologica. (2003) [Pubmed]
  6. The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Putney, L.K., Denker, S.P., Barber, D.L. Annu. Rev. Pharmacol. Toxicol. (2002) [Pubmed]
  7. Direct binding of the Na--H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Denker, S.P., Huang, D.C., Orlowski, J., Furthmayr, H., Barber, D.L. Mol. Cell (2000) [Pubmed]
  8. Endothelin-1 induced hypertrophic effect in neonatal rat cardiomyocytes: Involvement of Na(+)/H(+) and Na(+)/Ca(2+) exchangers. Dulce, R.A., Hurtado, C., Ennis, I.L., Garciarena, C.D., Alvarez, M.C., Caldiz, C., Pierce, G.N., Portiansky, E.L., Chiappe de Cingolani, G.E., Camili??n de Hurtado, M.C. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  9. CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. Bourguignon, L.Y., Singleton, P.A., Diedrich, F., Stern, R., Gilad, E. J. Biol. Chem. (2004) [Pubmed]
  10. Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium. Yokoyama, H., Gunasegaram, S., Harding, S.E., Avkiran, M. J. Am. Coll. Cardiol. (2000) [Pubmed]
  11. Uric acid as a cardiovascular risk factor in arterial hypertension. Puig, J.G., Ruilope, L.M. J. Hypertens. (1999) [Pubmed]
  12. Protection of the myocardial cell during ischemia. Théroux, P. Am. J. Cardiol. (1999) [Pubmed]
  13. A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange. Lin, X., Barber, D.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  14. The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival. Wu, K.L., Khan, S., Lakhe-Reddy, S., Jarad, G., Mukherjee, A., Obejero-Paz, C.A., Konieczkowski, M., Sedor, J.R., Schelling, J.R. J. Biol. Chem. (2004) [Pubmed]
  15. Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger. Pang, T., Wakabayashi, S., Shigekawa, M. J. Biol. Chem. (2002) [Pubmed]
  16. Localized Na+/H+ exchanger 1 expression protects Ca2+-regulated adenylyl cyclases from changes in intracellular pH. Willoughby, D., Masada, N., Crossthwaite, A.J., Ciruela, A., Cooper, D.M. J. Biol. Chem. (2005) [Pubmed]
  17. Interferon-gamma-induced STAT1-mediated membrane retention of NHE1 and associated proteins ezrin, radixin and moesin in HT-29 cells. Magro, F., Fraga, S., Soares-da-Silva, P. Biochem. Pharmacol. (2005) [Pubmed]
  18. Signaling of short- and long-term regulation of intestinal epithelial type 1 Na+/H+ exchanger by interferon-gamma. Magro, F., Fraga, S., Soares-da-Silva, P. Br. J. Pharmacol. (2005) [Pubmed]
  19. Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1. Mailänder, J., Müller-Esterl, W., Dedio, J. FEBS Lett. (2001) [Pubmed]
  20. Potent and selective inhibition of the human Na+/H+ exchanger isoform NHE1 by a novel aminoguanidine derivative T-162559. Kawamoto, T., Kimura, H., Kusumoto, K., Fukumoto, S., Shiraishi, M., Watanabe, T., Sawada, H. Eur. J. Pharmacol. (2001) [Pubmed]
  21. Structural and functional characterization of transmembrane segment IV of the NHE1 isoform of the Na+/H+ exchanger. Slepkov, E.R., Rainey, J.K., Li, X., Liu, Y., Cheng, F.J., Lindhout, D.A., Sykes, B.D., Fliegel, L. J. Biol. Chem. (2005) [Pubmed]
  22. A novel carbonic anhydrase II binding site regulates NHE1 activity. Li, X., Liu, Y., Alvarez, B.V., Casey, J.R., Fliegel, L. Biochemistry (2006) [Pubmed]
  23. Crystallization and preliminary crystallographic analysis of the human calcineurin homologous protein CHP2 bound to the cytoplasmic region of the Na+/H+ exchanger NHE1. Ben Ammar, Y., Takeda, S., Sugawara, M., Miyano, M., Mori, H., Wakabayashi, S. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2005) [Pubmed]
  24. Na(+)/H(+) exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes. Baumgartner, M., Patel, H., Barber, D.L. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  25. The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor. Yan, W., Nehrke, K., Choi, J., Barber, D.L. J. Biol. Chem. (2001) [Pubmed]
  26. The Na+-H+ exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells. Paradiso, A., Cardone, R.A., Bellizzi, A., Bagorda, A., Guerra, L., Tommasino, M., Casavola, V., Reshkin, S.J. Breast Cancer Res. (2004) [Pubmed]
  27. G alpha 13 stimulates Na+-H+ exchange through distinct Cdc42-dependent and RhoA-dependent pathways. Hooley, R., Yu, C.Y., Symons, M., Barber, D.L. J. Biol. Chem. (1996) [Pubmed]
  28. Regulation of intracellular pH in human melanoma: potential therapeutic implications. Wahl, M.L., Owen, J.A., Burd, R., Herlands, R.A., Nogami, S.S., Rodeck, U., Berd, D., Leeper, D.B., Owen, C.S. Mol. Cancer Ther. (2002) [Pubmed]
  29. Anion exchanger isoform 2 operates in parallel with Na(+)/H(+) exchanger isoform 1 during regulatory volume decrease of human cervical cancer cells. Shen, M.R., Wilkins, R.J., Chou, C.Y., Ellory, J.C. FEBS Lett. (2002) [Pubmed]
  30. Dexamethasone increases fluid absorption via Na+/H+ exchanger (NHE) 3 activation in normal human middle ear epithelial cells. Choi, J.Y., Kim, S.Y., Son, E.J., Kim, J.L., Shin, J.H., Song, M.H., Moon, U.Y., Yoon, J.H. Eur. J. Pharmacol. (2006) [Pubmed]
  31. Cloning and analysis of the human myocardial Na+/H+ exchanger. Fliegel, L., Dyck, J.R., Wang, H., Fong, C., Haworth, R.S. Mol. Cell. Biochem. (1993) [Pubmed]
  32. Immunofluorescence revealed the presence of NHE-1 in the nuclear membranes of rat cardiomyocytes and isolated nuclei of human, rabbit, and rat aortic and liver tissues. Bkaily, G., Nader, M., Avedanian, L., Jacques, D., Perrault, C., Abdel-Samad, D., D'Orléans-Juste, P., Gobeil, F., Hazzouri, K.M. Can. J. Physiol. Pharmacol. (2004) [Pubmed]
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