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SLC9A2  -  solute carrier family 9, subfamily A (NHE2...

Homo sapiens

Synonyms: NHE-2, NHE2, Na(+)/H(+) exchanger 2, Sodium/hydrogen exchanger 2, Solute carrier family 9 member 2
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Disease relevance of SLC9A2


High impact information on SLC9A2

  • Using isoform-specific primers, mRNA transcripts of the Na(+)/H(+) exchangers NHE1, NHE2, and NHE3 were detected by RT-PCR, and identities were confirmed by sequencing [6].
  • The strong predominance of DRA over NHE3 and NHE2 expression in duodenum was paralleled by much higher Cl-/HCO3- than Na+/H+ exchange rates in brush border membrane vesicles and likely explains the high duodenal HCO3- secretory rates [7].
  • NHE1 and NHE2 are not regulated by trafficking [8].
  • Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2) [9].
  • The role of the Pro-rich regions in subcellular targeting was examined by transfection of epitope-tagged forms of NHE2 in porcine renal epithelial LLC-PK1 cells [10].

Biological context of SLC9A2


Anatomical context of SLC9A2

  • The pharmacological profiles of these exchangers indicate that the human placental brush border membrane possesses the housekeeping or non-epithelial type Na(+)-H+ exchanger (NHE-1), whereas the basal membrane possesses the epithelial or apical type Na(+)-H+ exchanger (NHE-2) [13].
  • Human placental syncytiotrophoblast expresses two pharmacologically distinguishable types of Na(+)-H+ exchangers, NHE-1 in the maternal-facing (brush border) membrane and NHE-2 in the fetal-facing (basal) membrane [13].
  • Human NHE-2 is widely distributed in tissues of the gastrointestinal tract, kidney, heart, testes, uterus, and adrenal glands [11].
  • In addition, NHE-2 mRNA was present in surface epithelial cells as well as in cells of the crypt region, suggesting the presence of NHE-2 message throughout the vertical axis of the colonic crypts [14].
  • The NHE-2 message level in the distal colon was significantly higher than in the proximal colon but was evenly distributed in the small intestine [14].

Associations of SLC9A2 with chemical compounds

  • In C2 cells exposed to butyrate, acetate, proprionate, or the poorly metabolized SCFA isobutyrate, apical membrane NHE3 activity and protein expression increased in a time- and concentration-dependent manner, whereas no changes were observed for NHE2 [15].
  • Inhibition of NHE2 with 10(-5) M and 10(-4) M amiloride significantly increased net HCO(3)(-) output [16].
  • In addition, proximal duodenal mucosal HCO(3)(-) transport was measured in humans in vivo in response to luminal perfusion of graded doses of amiloride; 10(-5)--10(-4) M amiloride was used to inhibit NHE2 and 10(-3) M amiloride to inhibit NHE3 [16].
  • Thus, externally added Li+ activates NHE1 and NHE2 via a mechanism possibly involving a tyrosine kinase, causing an increase in cytoplasmic pH that could potentially affect various cell functions [17].
  • RESULTS: NHE activity was inhibited significantly (approximately 50%-75%, P < .05) by .1 micromol/L 5-HT via inhibition of maximal velocity (Vmax) without any changes in apparent affinity (Km) for the substrate Na+ . NHE inhibition involved a decrease of both NHE2 and NHE3 activities [18].

Physical interactions of SLC9A2

  • A PMA-induced nuclear factor that bound to the NHE2 promoter was identified as the transcription factor Egr-1 [19].

Regulatory relationships of SLC9A2


Other interactions of SLC9A2

  • Both NHE2 and NHE3 were localized principally to the brush border of duodenal villus cells [16].
  • However, NHE2 (p < 0.001) and GAPDH (p < 0.05) mRNA expression significantly increased 18- and 3.7-fold between early first trimester and term [21].
  • The expression of the isoforms NHE2 to NHE5 is restricted to specific tissues and the pattern of their expression, as well as their subcellular localization indicate that they fulfill specialized functions [22].
  • The NHE2 isoform of the Na+/H+ exchanger (NHE) displays two proline-rich sequences in its C-terminal region that resemble SH3 (Src homology 3)-binding domains [10].
  • 2. The activity of cysteine-sensitive alkaline phosphatase, and the abundance of villin, NHE2 and NHE3 proteins, markers of the colonic luminal membrane, were significantly enriched in the LMV compared with the original cellular homogenate [23].

Analytical, diagnostic and therapeutic context of SLC9A2


  1. Extensive genetic analysis of 10 candidate genes for hypertension in Japanese. Iwai, N., Kajimoto, K., Kokubo, Y., Tomoike, H. Hypertension (2006) [Pubmed]
  2. Na+/H+ exchanger isoforms NHE-2 and NHE-1 in inner medullary collecting duct cells. Expression, functional localization, and differential regulation. Soleimani, M., Singh, G., Bizal, G.L., Gullans, S.R., McAteer, J.A. J. Biol. Chem. (1994) [Pubmed]
  3. Prostaglandin-mediated inhibition of Na+/H+ exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine. Moeser, A.J., Nighot, P.K., Ryan, K.A., Wooten, J.G., Blikslager, A.T. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  4. Mechanisms of activation of NHE by cell shrinkage and by calyculin A in Ehrlich ascites tumor cells. Pederson, S.F., Varming, C., Christensen, S.T., Hoffmann, E.K. J. Membr. Biol. (2002) [Pubmed]
  5. The effect of environmental hypercapnia and salinity on the expression of NHE-like isoforms in the gills of a euryhaline fish (Fundulus heteroclitus). Edwards, S.L., Wall, B.P., Morrison-Shetlar, A., Sligh, S., Weakley, J.C., Claiborne, J.B. J. Exp. Zoolog. Part A Comp. Exp. Biol. (2005) [Pubmed]
  6. H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells. Thwaites, D.T., Ford, D., Glanville, M., Simmons, N.L. J. Clin. Invest. (1999) [Pubmed]
  7. Down-regulated in adenoma mediates apical Cl-/HCO3- exchange in rabbit, rat, and human duodenum. Jacob, P., Rossmann, H., Lamprecht, G., Kretz, A., Neff, C., Lin-Wu, E., Gregor, M., Groneberg, D.A., Kere, J., Seidler, U. Gastroenterology (2002) [Pubmed]
  8. Molecular physiology of intestinal Na+/H+ exchange. Zachos, N.C., Tse, M., Donowitz, M. Annu. Rev. Physiol. (2005) [Pubmed]
  9. Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2). Collins, J.F., Honda, T., Knobel, S., Bulus, N.M., Conary, J., DuBois, R., Ghishan, F.K. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  10. Proline-rich motifs of the Na+/H+ exchanger 2 isoform. Binding of Src homology domain 3 and role in apical targeting in epithelia. Chow, C.W., Woodside, M., Demaurex, N., Yu, F.H., Plant, P., Rotin, D., Grinstein, S., Orlowski, J. J. Biol. Chem. (1999) [Pubmed]
  11. Molecular cloning, sequencing, chromosomal localization, and tissue distribution of the human Na+/H+ exchanger (SLC9A2). Ghishan, F.K., Knobel, S.M., Summar, M. Genomics (1995) [Pubmed]
  12. The human Na(+)/H(+) exchanger NHE2 gene: genomic organization and promoter characterization. Malakooti, J., Dahdal, R.Y., Dudeja, P.K., Layden, T.J., Ramaswamy, K. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  13. Human placental syncytiotrophoblast expresses two pharmacologically distinguishable types of Na(+)-H+ exchangers, NHE-1 in the maternal-facing (brush border) membrane and NHE-2 in the fetal-facing (basal) membrane. Kulanthaivel, P., Furesz, T.C., Moe, A.J., Smith, C.H., Mahesh, V.B., Leibach, F.H., Ganapathy, V. Biochem. J. (1992) [Pubmed]
  14. Intestinal distribution of human Na+/H+ exchanger isoforms NHE-1, NHE-2, and NHE-3 mRNA. Dudeja, P.K., Rao, D.D., Syed, I., Joshi, V., Dahdal, R.Y., Gardner, C., Risk, M.C., Schmidt, L., Bavishi, D., Kim, K.E., Harig, J.M., Goldstein, J.L., Layden, T.J., Ramaswamy, K. Am. J. Physiol. (1996) [Pubmed]
  15. SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells. Musch, M.W., Bookstein, C., Xie, Y., Sellin, J.H., Chang, E.B. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  16. Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement. Repishti, M., Hogan, D.L., Pratha, V., Davydova, L., Donowitz, M., Tse, C.M., Isenberg, J.I. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  17. Lithium activates mammalian Na+/H+ exchangers: isoform specificity and inhibition by genistein. Kobayashi, Y., Pang, T., Iwamoto, T., Wakabayashi, S., Shigekawa, M. Pflugers Arch. (2000) [Pubmed]
  18. Serotonin inhibits Na+/H+ exchange activity via 5-HT4 receptors and activation of PKC alpha in human intestinal epithelial cells. Gill, R.K., Saksena, S., Tyagi, S., Alrefai, W.A., Malakooti, J., Sarwar, Z., Turner, J.R., Ramaswamy, K., Dudeja, P.K. Gastroenterology (2005) [Pubmed]
  19. Zinc finger transcription factor Egr-1 is involved in stimulation of NHE2 gene expression by phorbol 12-myristate 13-acetate. Malakooti, J., Sandoval, R., Memark, V.C., Dudeja, P.K., Ramaswamy, K. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  20. Protein kinase C-alpha regulation of gallbladder Na+ transport becomes progressively more dysfunctional during gallstone formation. Narins, S.C., Ramakrishnan, R., Park, E.H., Bolno, P.B., Haggerty, D.A., Smith, P.R., Meyers, W.C., Abedin, M.Z. J. Lab. Clin. Med. (2005) [Pubmed]
  21. Gestational profile of Na+/H+ exchanger and Cl-/HCO3- anion exchanger mRNA expression in placenta using real-time QPCR. Lacey, H.A., Nolan, T., Greenwood, S.L., Glazier, J.D., Sibley, C.P. Placenta (2005) [Pubmed]
  22. Na(+)/H(+)exchangers: linking osmotic dysequilibrium to modified cell function. Ritter, M., Fuerst, J., Wöll, E., Chwatal, S., Gschwentner, M., Lang, F., Deetjen, P., Paulmichl, M. Cell. Physiol. Biochem. (2001) [Pubmed]
  23. The characterization of butyrate transport across pig and human colonic luminal membrane. Ritzhaupt, A., Ellis, A., Hosie, K.B., Shirazi-Beechey, S.P. J. Physiol. (Lond.) (1998) [Pubmed]
  24. Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2. Malakooti, J., Dahdal, R.Y., Schmidt, L., Layden, T.J., Dudeja, P.K., Ramaswamy, K. Am. J. Physiol. (1999) [Pubmed]
  25. Na+/H+ exchange activity during phagocytosis in human neutrophils: role of Fcgamma receptors and tyrosine kinases. Fukushima, T., Waddell, T.K., Grinstein, S., Goss, G.G., Orlowski, J., Downey, G.P. J. Cell Biol. (1996) [Pubmed]
  26. Activity and protein expression of the Na+/H+ exchanger is reduced in syncytiotrophoblast microvillous plasma membranes isolated from preterm intrauterine growth restriction pregnancies. Johansson, M., Glazier, J.D., Sibley, C.P., Jansson, T., Powell, T.L. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  27. Expression of Na+/H+ exchanger isoforms in normal human nasal epithelial cells and functional activity of Na+/H+ exchanger 1 in intracellular pH regulation. Shin, J.H., Namkung, W., Kim, C.H., Choi, J.Y., Yoo, J.B., Lee, K.D., Lee, J.G., Lee, M.G., Yoon, J.H. Acta Otolaryngol. (2005) [Pubmed]
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