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Gene Review

Slc9a1  -  solute carrier family 9, subfamily A (NHE1...

Rattus norvegicus

Synonyms: NHE-1, Na(+)/H(+) exchanger 1, Nhe1, Sodium/hydrogen exchanger 1, Solute carrier family 9 member 1
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Disease relevance of Slc9a1

  • Activity of the Na+/H+ exchanger (NHE) isoform 1 (NHE1) is increased by intracellular acidosis through the interaction of intracellular H+ with an allosteric modifier site in the transport domain [1].
  • These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt [2].
  • CONCLUSIONS: These results indicate an important contribution of both ET-1 and NHE-1 in the pathogenesis of diabetic cardiomyopathy [3].
  • Both hypertrophy and elevated Na+ levels were prevented by the NHE-1-specific inhibitor EMD87580 as well as the aldosterone antagonist spironolactone, although the increased NHE-1 levels were prevented only by spironolactone [4].
  • Increased activity of the cellular Na(+)-H+ exchangers (NHEs), especially isoform 1 (NHE-1), is a recognized intermediate phenotype of hypertension [5].

Psychiatry related information on Slc9a1


High impact information on Slc9a1

  • NHE-3 transport activity was measured as the initial proton flux rate calculated from the Na-dependent cell pH recovery of Na-depleted acidified MTAL cells in the presence of 50 microM HOE694 which specifically blocks NHE-1, the basolateral MTAL NHE isoform [8].
  • Northern analysis of VSMC poly A+ RNA revealed that high glucose induced a threefold increase in Na+/H+ antiport (NHE-1) mRNA at 24 h [9].
  • Inhibiting this increase in NHE-1 mRNA with actinomycin D prevented the sustained glucose-induced increase in Na+/H+ antiport activity [9].
  • The permeant carbonic anhydrase (CA) inhibitor methazolamide, relatively impermeant CA inhibitor benzolamide, vanilloid receptor antagonist capsazepine, or sodium-hydrogen exchanger 1 (NHE-1) inhibitor dimethyl amiloride were perfused with or without the high CO(2) solution [10].
  • NHE-1 activation preceding TRPV1 stimulation suggests that luminal CO(2) is sensed as H(+) in the subepithelium [10].

Chemical compound and disease context of Slc9a1

  • Sustained (3 min) intracellular acidosis activated several NHE1 kinases in NRVM, in an in-gel kinase assay using as substrate a glutathione S-transferase fusion protein of the NHE1 regulatory domain [1].
  • That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration [2].
  • The objective of this study was to examine the expression of the NHE-1 isoform during colitis induced by acetic acid or trinitrobenzenesulfonic acid in Sprague-Dawley male rats [11].
  • 2K-1C animals showed high BP, increased serum concentration of PGE2 and TxB2, hypertrophy of the unclipped kidneys, but not in the clipped kidneys In addition, NHE-1 and NHE-3 isoforms were increased in both the 2K-1C kidneys, whereas alpha-actin was increased in the clipped but not in unclipped kidneys [12].
  • NHE-1 mRNA from the cortex of the ADR rats progressively increased at weeks 4 and 8 and then peaked at week 16, which paralleled with the degree of glomerular sclerosis and interstitial fibrosis [13].

Biological context of Slc9a1

  • Based on the deduced amino acid sequences, NHE-1, -3, and -4 are similar in size, having relative molecular masses of 91,506, 92,997, and 81,427, respectively [14].
  • OBJECTIVES: Expression of NHE-1 and NHE-3 isoforms and sodium pump activity (PNP), and their modulation by blood pressure (BP), PGE(2) and TXB(2) were examined in the kidneys of 2K-1C rats treated with cilazapril for short- (4 and 24 h) and long-term (7 days) periods [15].
  • Immunoprecipitation experiments revealed that, although NHE-1 was phosphorylated in the resting state, no further phosphorylation occurred upon treatment with carbachol [16].
  • Moreover, a functional interaction occurred with Na+/H+ exchange (NHE) consistent with colocation of K+/H+ antiport and apical NHE-3, not basolateral NHE-1 [17].
  • To examine their intrinsic responsiveness to G protein and second messenger stimulation, three of these isoforms, NHE-1, -2, and -3, were stably expressed in mutant Chinese hamster ovary cells devoid of endogenous NHE activity (AP-1 cells) [18].

Anatomical context of Slc9a1

  • Stimulation of the plasma membrane Na+/H+ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway [1].
  • The purposes of this study were to test 1) the relationship between two widely studied mitogenic effector pathways, and 2) the hypothesis that sodium-proton exchanger type 1 (NHE-1) is a regulator of extracellular signal-regulated protein kinase (ERK) activation in rat aortic smooth muscle (RASM) cells [19].
  • The basolateral NHE1 Na+/H+ exchanger regulates transepithelial HCO3- absorption through actin cytoskeleton remodeling in renal thick ascending limb [20].
  • These data suggest that NHE-1 may act as a downstream mediator in the production of ET-induced functional and structural changes in the myocardium in diabetes [3].
  • NHE-1 was localized in the endothelium of the retinal microvasculature and the neuronal and glial components [21].

Associations of Slc9a1 with chemical compounds

  • To examine the mechanisms involved in regulating expression of the Na+/H+ exchanger, we have characterized the regulation of a distal element of the NHE1 promoter by the thyroid hormone receptor [22].
  • Jasplakinolide had no effect on HCO3- absorption in tubules bathed with amiloride or a Na(+)-free bath to inhibit NHE1 [20].
  • Vasopressin, which inhibits HCO3- absorption by an amount similar to that observed with amiloride and NGF but does not act via NHE1, did not affect cellular F-actin content [20].
  • Inhibition of NHE-1 with pharmacological agents or by isotonic replacement of sodium in the perfusate with choline or tetramethylammonium greatly attenuated ERK activation by 5-HT or Ang II [19].
  • While cAMP enhances TRC apical H(+) entry and CT responses to strong acid, an increase in Ca(2+) activates NHE-1, and increases neural adaptation to all acidic stimuli [23].

Physical interactions of Slc9a1

  • The calmodulin (CaM)-binding domain reduces the affinity of the Na+/H+ exchanger NHE1 for intracellular H+ by exerting an autoinhibitory function in quiescent cells [24].

Regulatory relationships of Slc9a1

  • These results indicate that basolateral NHE1 regulates apical NHE3 and HCO3- absorption in the MTAL by controlling the organization of the actin cytoskeleton [20].
  • As a functional correlate of increased 11betaHSD-2 expression in colon, the GR-stimulated sodium-hydrogen exchanger NHE-3 was lowered by NaCl restriction [25].
  • CONCLUSIONS: Angiotensin II via its AT1 and AT2 receptors differentially controls transcriptional and translational regulation as well as the activity of NHE-1 and NBC-1 in the ischemic myocardium and contributes to the control of pH regulation in cardiac tissue [26].
  • And contrary to an earlier finding, ectopic coexpression of CHP3 up-regulated the cell surface activity of wild-type NHE1 [27].

Other interactions of Slc9a1

  • CONCLUSIONS: These findings demonstrate a differential expression of NHE-1 and NHE-3 isoforms which is dependent on the rise in BP, PGE(2) or TXB(2) in the long-term treatment group, but not in the short-term treatment group [15].
  • Contributions of endothelin-1 and sodium hydrogen exchanger-1 in the diabetic myocardium [3].
  • Conserved motifs in somatostatin, D2-dopamine, and alpha 2B-adrenergic receptors for inhibiting the Na-H exchanger, NHE1 [28].
  • We identified conserved motifs within intracellular domains 2 and 3 of selective subtypes of several G protein-coupled receptor families that confer coupling to the Na-H exchanger, NHE1 [28].
  • Detailed investigation of ERK and its downstream effector p90RSK, two putative NHE1 kinases, revealed time-dependent activation of both by intracellular acidosis in NRVM [1].

Analytical, diagnostic and therapeutic context of Slc9a1


  1. Stimulation of the plasma membrane Na+/H+ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. Haworth, R.S., McCann, C., Snabaitis, A.K., Roberts, N.A., Avkiran, M. J. Biol. Chem. (2003) [Pubmed]
  2. Mineralocorticoid action and sodium-hydrogen exchange: studies in experimental cardiac fibrosis. Young, M., Funder, J. Endocrinology (2003) [Pubmed]
  3. Contributions of endothelin-1 and sodium hydrogen exchanger-1 in the diabetic myocardium. Hileeto, D., Cukiernik, M., Mukherjee, S., Evans, T., Barbin, Y., Downey, D., Karmazyn, M., Chakrabarti, S. Diabetes Metab. Res. Rev. (2002) [Pubmed]
  4. Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes. Karmazyn, M., Liu, Q., Gan, X.T., Brix, B.J., Fliegel, L. Hypertension (2003) [Pubmed]
  5. Activity and expression of Na(+)-H+ exchanger isoforms 1 and 3 in kidney proximal tubules of hypertensive rats. Kelly, M.P., Quinn, P.A., Davies, J.E., Ng, L.L. Circ. Res. (1997) [Pubmed]
  6. Activity of the Na(+)/H(+) exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart. Xiao, X.H., Allen, D.G. Cardiovasc. Res. (2000) [Pubmed]
  7. Functional observational battery and motor activity in rats after single administration of two NHE 1 inhibitors. Hübler, N., Gottschling, B., Jacobs, M., von Landenberg, F., Hewicker-Trautwein, M. Toxicol. Appl. Pharmacol. (2005) [Pubmed]
  8. Chronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA. Laghmani, K., Borensztein, P., Ambühl, P., Froissart, M., Bichara, M., Moe, O.W., Alpern, R.J., Paillard, M. J. Clin. Invest. (1997) [Pubmed]
  9. Glucose-induced changes in Na+/H+ antiport activity and gene expression in cultured vascular smooth muscle cells. Role of protein kinase C. Williams, B., Howard, R.L. J. Clin. Invest. (1994) [Pubmed]
  10. Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum. Akiba, Y., Ghayouri, S., Takeuchi, T., Mizumori, M., Guth, P.H., Engel, E., Swenson, E.R., Kaunitz, J.D. Gastroenterology (2006) [Pubmed]
  11. Colitis-induced changes in the expression of the Na+/H+ exchanger isoform NHE-1. Khan, I., al-Awadi, F.M., Abul, H. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  12. Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible mediation of Na/H exchanger isoform-1. Al-Qattan, K.K., Khan, I., Alnaqeeb, M.A., Ali, M. Prostaglandins Leukot. Essent. Fatty Acids (2003) [Pubmed]
  13. Increased expression of Na+/H+ exchanger in the injured renal tissues of focal glomerulosclerosis in rats. Okuda, S., Tamaki, K., Ando, T., Nagashima, A., Nakayama, M., Fukuda, K., Higashi, H., Fujishima, M. Kidney Int. (1994) [Pubmed]
  14. 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. Orlowski, J., Kandasamy, R.A., Shull, G.E. J. Biol. Chem. (1992) [Pubmed]
  15. Altered expression of Na(+)/H(+) exchanger isoforms 1 and 3 in clipped and unclipped kidneys of a 2-kidney-1-clip Goldblatt model of hypertension. Khan, I., Al-Qattan, K.K., Alnaqeeb, M.A., Ali, M. Nephron (2002) [Pubmed]
  16. Muscarinic agonists induce phosphorylation-independent activation of the NHE-1 isoform of the Na+/H+ antiporter in salivary acinar cells. Robertson, M.A., Woodside, M., Foskett, J.K., Orlowski, J., Grinstein, S. J. Biol. Chem. (1997) [Pubmed]
  17. Apical location and inhibition by arginine vasopressin of K+/H+ antiport of the medullary thick ascending limb of rat kidney. Attmane-Elakeb, A., Boulanger, H., Vernimmen, C., Bichara, M. J. Biol. Chem. (1997) [Pubmed]
  18. Plasma membrane Na+/H+ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways. Kandasamy, R.A., Yu, F.H., Harris, R., Boucher, A., Hanrahan, J.W., Orlowski, J. J. Biol. Chem. (1995) [Pubmed]
  19. ERK is regulated by sodium-proton exchanger in rat aortic vascular smooth muscle cells. Mukhin, Y.V., Garnovskaya, M.N., Ullian, M.E., Raymond, J.R. J. Biol. Chem. (2004) [Pubmed]
  20. The basolateral NHE1 Na+/H+ exchanger regulates transepithelial HCO3- absorption through actin cytoskeleton remodeling in renal thick ascending limb. Watts, B.A., George, T., Good, D.W. J. Biol. Chem. (2005) [Pubmed]
  21. The role of the sodium hydrogen exchanger-1 in mediating diabetes-induced changes in the retina. Cukiernik, M., Hileeto, D., Downey, D., Evans, T., Khan, Z.A., Karmazyn, M., Chakrabarti, S. Diabetes Metab. Res. Rev. (2004) [Pubmed]
  22. Thyroid hormone receptor alpha 1 regulates expression of the Na+/H+ exchanger (NHE1). Li, X., Misik, A.J., Rieder, C.V., Solaro, R.J., Lowen, A., Fliegel, L. J. Biol. Chem. (2002) [Pubmed]
  23. Basolateral Na+-H+ exchanger-1 in rat taste receptor cells is involved in neural adaptation to acidic stimuli. Lyall, V., Alam, R.I., Malik, S.A., Phan, T.H., Vinnikova, A.K., Heck, G.L., DeSimone, J.A. J. Physiol. (Lond.) (2004) [Pubmed]
  24. Calmodulin-binding autoinhibitory domain controls "pH-sensing" in the Na+/H+ exchanger NHE1 through sequence-specific interaction. Wakabayashi, S., Ikeda, T., Iwamoto, T., Pouysségur, J., Shigekawa, M. Biochemistry (1997) [Pubmed]
  25. Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake. Nørregaard, R., Uhrenholt, T.R., Bistrup, C., Skøtt, O., Jensen, B.L. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  26. Differential effects of angiotensin AT1 and AT2 receptors on the expression, translation and function of the Na+-H+ exchanger and Na+-HCO3- symporter in the rat heart after myocardial infarction. Sandmann, S., Yu, M., Kaschina, E., Blume, A., Bouzinova, E., Aalkjaer, C., Unger, T. J. Am. Coll. Cardiol. (2001) [Pubmed]
  27. Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform. Zaun, H.C., Shrier, A., Orlowski, J. J. Biol. Chem. (2008) [Pubmed]
  28. Conserved motifs in somatostatin, D2-dopamine, and alpha 2B-adrenergic receptors for inhibiting the Na-H exchanger, NHE1. Lin, C.Y., Varma, M.G., Joubel, A., Madabushi, S., Lichtarge, O., Barber, D.L. J. Biol. Chem. (2003) [Pubmed]
  29. Na(+)-H+ exchanger expression in vascular smooth muscle of spontaneously hypertensive and Wistar-Kyoto rats. Lucchesi, P.A., DeRoux, N., Berk, B.C. Hypertension (1994) [Pubmed]
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