Sodium–hydrogen antiporter 1 explained

The sodium-hydrogen antiporter 1 (NHE-1) also known as sodium/hydrogen exchanger 1 or SLC9A1 (SoLute Carrier family 9A1) is an isoform of sodium–hydrogen antiporter that in humans is encoded by the SLC9A1 gene.^[1]

Function

The Na⁺/H⁺ antiporter (SLC9A1) is a ubiquitous membrane-bound enzyme involved in volume- and pH-regulation of vertebrate cells. It is inhibited by the non-specific diuretic drug amiloride and activated by a variety of signals including growth factors, mitogens, neurotransmitters, tumor promoters, and others.^[2]

Interactions

Sodium–hydrogen antiporter 1 has been shown to interact with carbonic anhydrase II^[3] and CHP.^{[4] [5] [6]} It is also the target of the experimental drug rimeporide, which is being developed for the treatment of Duchenne muscular dystrophy.^[7]

Further reading

• Yu L, Quinn DA, Garg HG, Hales CA . Deficiency of the NHE1 gene prevents hypoxia-induced pulmonary hypertension and vascular remodeling . American Journal of Respiratory and Critical Care Medicine . 177 . 11 . 1276–84 . June 2008 . 18310478 . 2408441 . 10.1164/rccm.200710-1522OC .
• Rios EJ, Fallon M, Wang J, Shimoda LA . Chronic hypoxia elevates intracellular pH and activates Na+/H+ exchange in pulmonary arterial smooth muscle cells . American Journal of Physiology. Lung Cellular and Molecular Physiology . 289 . 5 . L867–74 . November 2005 . 15964895 . 10.1152/ajplung.00455.2004 . 16399637 .
• Cingolani HE, Ennis IL . Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy . Circulation . 115 . 9 . 1090–100 . March 2007 . 17339567 . 10.1161/CIRCULATIONAHA.106.626929 . free .
• Meima ME, Mackley JR, Barber DL . Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1 . Current Opinion in Nephrology and Hypertension . 16 . 4 . 365–72 . July 2007 . 17565280 . 10.1097/MNH.0b013e3281bd888d . 25616109 .
• Tse CM, Ma AI, Yang VW, Watson AJ, Levine S, Montrose MH, Potter J, Sardet C, Pouyssegur J, Donowitz M . 6 . Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger . The EMBO Journal . 10 . 8 . 1957–67 . August 1991 . 1712287 . 452875 . 10.1002/j.1460-2075.1991.tb07725.x .
• Dudley CR, Giuffra LA, Tippett P, Kidd KK, Reeders ST . The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1 . Human Genetics . 86 . 1 . 79–83 . November 1990 . 1979310 . 10.1007/bf00205179 . 20107780 .
• Sardet C, Counillon L, Franchi A, Pouysségur J . Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD . Science . 247 . 4943 . 723–6 . February 1990 . 2154036 . 10.1126/science.2154036 . 1990Sci...247..723S .
• Sardet C, Franchi A, Pouysségur J . Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter . Cell . 56 . 2 . 271–80 . January 1989 . 2536298 . 10.1016/0092-8674(89)90901-X . 2782563 .
• Mattei MG, Sardet C, Franchi A, Pouysségur J . The human amiloride-sensitive Na+/H+ antiporter: localization to chromosome 1 by in situ hybridization . Cytogenetics and Cell Genetics . 48 . 1 . 6–8 . 1988 . 2846238 . 10.1159/000132575 .
• Counillon L, Pouysségur J, Reithmeier RA . The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain . Biochemistry . 33 . 34 . 10463–9 . August 1994 . 8068684 . 10.1021/bi00200a030 .
• Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS . Cloning and analysis of the human myocardial Na+/H+ exchanger . Molecular and Cellular Biochemistry . 125 . 2 . 137–43 . August 1993 . 8283968 . 10.1007/BF00936442 . 24360200 .
• Lin X, Barber DL . A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange . Proceedings of the National Academy of Sciences of the United States of America . 93 . 22 . 12631–6 . October 1996 . 8901634 . 38044 . 10.1073/pnas.93.22.12631 . 1996PNAS...9312631L . free .
• Shrode LD, Gan BS, D'Souza SJ, Orlowski J, Grinstein S . Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage . The American Journal of Physiology . 275 . 2 . C431-9 . August 1998 . 9688597 . 10.1152/ajpcell.1998.275.2.C431 . free .
• Wakabayashi S, Pang T, Su X, Shigekawa M . A novel topology model of the human Na(+)/H(+) exchanger isoform 1 . The Journal of Biological Chemistry . 275 . 11 . 7942–9 . March 2000 . 10713111 . 10.1074/jbc.275.11.7942 . free .
• Garden OA, Musk P, Worthington-White DA, Dewey MJ, Rich IN . Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: A comparison with healthy controls . Cancer Genetics and Cytogenetics . 120 . 1 . 37–43 . July 2000 . 10913675 . 10.1016/S0165-4608(99)00246-0 .
• Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL . Direct binding of the Na--H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation . Molecular Cell . 6 . 6 . 1425–36 . December 2000 . 11163215 . 10.1016/S1097-2765(00)00139-8 . free .
• Lehoux S, Florian JA, Berk BC . 14-3-3 Binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange . The Journal of Biological Chemistry . 276 . 19 . 15794–800 . May 2001 . 11279064 . 10.1074/jbc.M100410200 . free .
• Pang T, Su X, Wakabayashi S, Shigekawa M . Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers . The Journal of Biological Chemistry . 276 . 20 . 17367–72 . May 2001 . 11350981 . 10.1074/jbc.M100296200 . free .
• Yan W, Nehrke K, Choi J, Barber DL . The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor . The Journal of Biological Chemistry . 276 . 33 . 31349–56 . August 2001 . 11369779 . 10.1074/jbc.M102679200 . free .
• Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, Fisher RJ, Fliegel L, Durum SK . 6 . Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization . Molecular and Cellular Biology . 21 . 22 . 7545–57 . November 2001 . 11604491 . 99926 . 10.1128/MCB.21.22.7545-7557.2001 .
• Mailänder J, Müller-Esterl W, Dedio J . Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1 . FEBS Letters . 507 . 3 . 331–5 . November 2001 . 11696366 . 10.1016/S0014-5793(01)02986-6 . 23406238 .
• Shen MR, Wilkins RJ, Chou CY, Ellory JC . Anion exchanger isoform 2 operates in parallel with Na(+)/H(+) exchanger isoform 1 during regulatory volume decrease of human cervical cancer cells . FEBS Letters . 512 . 1–3 . 52–8 . February 2002 . 11852051 . 10.1016/S0014-5793(01)03317-8 . free .
• Behne MJ, Meyer JW, Hanson KM, Barry NP, Murata S, Crumrine D, Clegg RW, Gratton E, Holleran WM, Elias PM, Mauro TM . 6 . NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging . The Journal of Biological Chemistry . 277 . 49 . 47399–406 . December 2002 . 12221084 . 10.1074/jbc.M204759200 . free .

Notes and References

1. Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS . Cloning and analysis of the human myocardial Na+/H+ exchanger . Molecular and Cellular Biochemistry . 125 . 2 . 137–43 . August 1993 . 8283968 . 10.1007/BF00936442 . 24360200 .
2. Cardone RA, Alfarouk KO, Elliott RL, Alqahtani SS, Ahmed SB, Aljarbou AN, Greco MR, Cannone S, Reshkin SJ . 6 . The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela . International Journal of Molecular Sciences . 20 . 15 . 3694 . July 2019 . 31357694 . 6696090 . 10.3390/ijms20153694 . free .
3. Li X, Alvarez B, Casey JR, Reithmeier RA, Fliegel L . Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger . The Journal of Biological Chemistry . 277 . 39 . 36085–91 . September 2002 . 12138085 . 10.1074/jbc.M111952200 . free .
4. Inoue H, Nakamura Y, Nagita M, Takai T, Masuda M, Nakamura N, Kanazawa H . Calcineurin homologous protein isoform 2 (CHP2), Na+/H+ exchangers-binding protein, is expressed in intestinal epithelium . Biological & Pharmaceutical Bulletin . 26 . 2 . 148–55 . February 2003 . 12576672 . 10.1248/bpb.26.148 . free .
5. Lin X, Barber DL . A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange . Proceedings of the National Academy of Sciences of the United States of America . 93 . 22 . 12631–6 . October 1996 . 8901634 . 38044 . 10.1073/pnas.93.22.12631 . 1996PNAS...9312631L . free .
6. Pang T, Su X, Wakabayashi S, Shigekawa M . Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers . The Journal of Biological Chemistry . 276 . 20 . 17367–72 . May 2001 . 11350981 . 10.1074/jbc.M100296200 . free .
7. Österreichische Apothekerzeitung. 69. 11. 12. Rimeporide. Helmut. Spreitzer. 26 May 2015. German.