Sodium–hydrogen antiporter 1

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.[5]

SLC9A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Y4E, 2BEC, 2E30, 2KBV, 2L0E, 2MDF, 2YGG
Identifiers
Aliases	SLC9A1, APNH, NHE-1, NHE1, PPP1R143, LIKNS, Sodium–hydrogen antiporter 1, solute carrier family 9 member A1
External IDs	OMIM: 107310 MGI: 102462 HomoloGene: 20660 GeneCards: SLC9A1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.11 Start 27,098,809 bp[1] End 27,166,981 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 D2.3|4 66.25 cM Start 133,369,706 bp[2] End 133,423,702 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein binding, bridging • calcium-dependent protein binding • phosphatidylinositol-4,5-bisphosphate binding • antiporter activity • solute:proton antiporter activity • sodium:proton antiporter activity involved in regulation of cardiac muscle cell membrane potential • calmodulin binding • GO:0001948 protein binding • GO:0032947 molecular adaptor activity • protein phosphatase 2B binding • sodium:proton antiporter activity • potassium:proton antiporter activity Cellular component • cytoplasm • membrane • focal adhesion • T-tubule • mitochondrion • perinuclear region of cytoplasm • cation-transporting ATPase complex • cell surface • apical plasma membrane • endoplasmic reticulum • membrane raft • extracellular exosome • lamellipodium • integral component of membrane • intercalated disc • cell membrane • nucleoplasm • endoplasmic reticulum membrane • integral component of plasma membrane • basolateral plasma membrane • sarcolemma Biological process • regulation of cardiac muscle contraction by calcium ion signaling • regulation of sensory perception of pain • positive regulation of the force of heart contraction • positive regulation of cardiac muscle hypertrophy • cellular response to epinephrine stimulus • positive regulation of action potential • cellular response to mechanical stimulus • maintenance of cell polarity • cellular response to hypoxia • positive regulation of mitochondrial membrane permeability • response to muscle stretch • hydrogen ion transmembrane transport • cellular sodium ion homeostasis • cardiac muscle cell differentiation • ion transport • positive regulation of cell growth • cellular response to insulin stimulus • regulation of focal adhesion assembly • regulation of cardiac muscle cell membrane potential • response to acidic pH • cell differentiation • regulation of the force of heart contraction • cellular response to organic cyclic compound • cellular response to acidic pH • cation transport • negative regulation of apoptotic process • regulation of the force of heart contraction by cardiac conduction • regulation of pH • cardiac muscle cell contraction • neuron death • hyaluronan catabolic process • response to organic cyclic compound • sodium ion transport • regulation of intracellular pH • GO:0010740 positive regulation of intracellular signal transduction • regulation of stress fiber assembly • positive regulation of calcineurin-NFAT signaling cascade • protein oligomerization • sodium ion import across plasma membrane • positive regulation of apoptotic process • cellular response to antibiotic • positive regulation of calcium:sodium antiporter activity • cell migration • positive regulation of transcription from RNA polymerase II promoter • cellular response to electrical stimulus • potassium ion transmembrane transport • transmembrane transport • transport • cellular response to cold • sodium ion export from cell • anion transmembrane transport • sodium ion transmembrane transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6548	20544
Ensembl	ENSG00000090020	ENSMUSG00000028854
UniProt	P19634	Q61165
RefSeq (mRNA)	NM_003047	NM_016981 NM_001358455
RefSeq (protein)	NP_003038	NP_058677 NP_001345384
Location (UCSC)	Chr 1: 27.1 – 27.17 Mb	Chr 4: 133.37 – 133.42 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[6]

Interactions

Sodium–hydrogen antiporter 1 has been shown to interact with carbonic anhydrase II[7] and CHP.[8][9][10] It is also the target of the experimental drug rimeporide, which is being developed for the treatment of Duchenne muscular dystrophy.[11]

References

1. GRCh38: Ensembl release 89: ENSG00000090020 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028854 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS (August 1993). "Cloning and analysis of the human myocardial Na+/H+ exchanger". Molecular and Cellular Biochemistry. 125 (2): 137–43. doi:10.1007/BF00936442. PMID 8283968.
6. Cardone RA, Alfarouk KO, Elliott RL, Alqahtani SS, Ahmed SB, Aljarbou AN, et al. (July 2019). "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. doi:10.3390/ijms20153694. PMC 6696090. PMID 31357694.
7. Li X, Alvarez B, Casey JR, Reithmeier RA, Fliegel L (September 2002). "Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger". The Journal of Biological Chemistry. 277 (39): 36085–91. doi:10.1074/jbc.M111952200. PMID 12138085.
8. Inoue H, Nakamura Y, Nagita M, Takai T, Masuda M, Nakamura N, Kanazawa H (February 2003). "Calcineurin homologous protein isoform 2 (CHP2), Na+/H+ exchangers-binding protein, is expressed in intestinal epithelium". Biological & Pharmaceutical Bulletin. 26 (2): 148–55. doi:10.1248/bpb.26.148. PMID 12576672.
9. Lin X, Barber DL (October 1996). "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. Bibcode:1996PNAS...9312631L. doi:10.1073/pnas.93.22.12631. PMC 38044. PMID 8901634.
10. Pang T, Su X, Wakabayashi S, Shigekawa M (May 2001). "Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers". The Journal of Biological Chemistry. 276 (20): 17367–72. doi:10.1074/jbc.M100296200. PMID 11350981.
11. Spreitzer, Helmut (26 May 2015). "Rimeporide". Österreichische Apothekerzeitung (in German). 69 (11): 12.

Further reading

• Yu L, Quinn DA, Garg HG, Hales CA (June 2008). "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. doi:10.1164/rccm.200710-1522OC. PMC 2408441. PMID 18310478.
• Rios EJ, Fallon M, Wang J, Shimoda LA (November 2005). "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. doi:10.1152/ajplung.00455.2004. PMID 15964895.
• Cingolani HE, Ennis IL (March 2007). "Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy". Circulation. 115 (9): 1090–100. doi:10.1161/CIRCULATIONAHA.106.626929. PMID 17339567.
• Meima ME, Mackley JR, Barber DL (July 2007). "Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1". Current Opinion in Nephrology and Hypertension. 16 (4): 365–72. doi:10.1097/MNH.0b013e3281bd888d. PMID 17565280.
• Tse CM, Ma AI, Yang VW, Watson AJ, Levine S, Montrose MH, et al. (August 1991). "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. doi:10.1002/j.1460-2075.1991.tb07725.x. PMC 452875. PMID 1712287.
• Dudley CR, Giuffra LA, Tippett P, Kidd KK, Reeders ST (November 1990). "The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1". Human Genetics. 86 (1): 79–83. doi:10.1007/bf00205179. PMID 1979310.
• Sardet C, Counillon L, Franchi A, Pouysségur J (February 1990). "Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD". Science. 247 (4943): 723–6. Bibcode:1990Sci...247..723S. doi:10.1126/science.2154036. PMID 2154036.
• Sardet C, Franchi A, Pouysségur J (January 1989). "Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter". Cell. 56 (2): 271–80. doi:10.1016/0092-8674(89)90901-X. PMID 2536298.
• Mattei MG, Sardet C, Franchi A, Pouysségur J (1988). "The human amiloride-sensitive Na+/H+ antiporter: localization to chromosome 1 by in situ hybridization". Cytogenetics and Cell Genetics. 48 (1): 6–8. doi:10.1159/000132575. PMID 2846238.
• Counillon L, Pouysségur J, Reithmeier RA (August 1994). "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. doi:10.1021/bi00200a030. PMID 8068684.
• Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS (August 1993). "Cloning and analysis of the human myocardial Na+/H+ exchanger". Molecular and Cellular Biochemistry. 125 (2): 137–43. doi:10.1007/BF00936442. PMID 8283968.
• Lin X, Barber DL (October 1996). "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. Bibcode:1996PNAS...9312631L. doi:10.1073/pnas.93.22.12631. PMC 38044. PMID 8901634.
• Shrode LD, Gan BS, D'Souza SJ, Orlowski J, Grinstein S (August 1998). "Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage". The American Journal of Physiology. 275 (2): C431-9. doi:10.1152/ajpcell.1998.275.2.C431. PMID 9688597.
• Wakabayashi S, Pang T, Su X, Shigekawa M (March 2000). "A novel topology model of the human Na(+)/H(+) exchanger isoform 1". The Journal of Biological Chemistry. 275 (11): 7942–9. doi:10.1074/jbc.275.11.7942. PMID 10713111.
• Garden OA, Musk P, Worthington-White DA, Dewey MJ, Rich IN (July 2000). "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. doi:10.1016/S0165-4608(99)00246-0. PMID 10913675.
• Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (December 2000). "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. doi:10.1016/S1097-2765(00)00139-8. PMID 11163215.
• Lehoux S, Florian JA, Berk BC (May 2001). "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. doi:10.1074/jbc.M100410200. PMID 11279064.
• Pang T, Su X, Wakabayashi S, Shigekawa M (May 2001). "Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers". The Journal of Biological Chemistry. 276 (20): 17367–72. doi:10.1074/jbc.M100296200. PMID 11350981.
• Yan W, Nehrke K, Choi J, Barber DL (August 2001). "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. doi:10.1074/jbc.M102679200. PMID 11369779.
• Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, et al. (November 2001). "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization". Molecular and Cellular Biology. 21 (22): 7545–57. doi:10.1128/MCB.21.22.7545-7557.2001. PMC 99926. PMID 11604491.
• Mailänder J, Müller-Esterl W, Dedio J (November 2001). "Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1". FEBS Letters. 507 (3): 331–5. doi:10.1016/S0014-5793(01)02986-6. PMID 11696366.
• Shen MR, Wilkins RJ, Chou CY, Ellory JC (February 2002). "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. doi:10.1016/S0014-5793(01)03317-8. PMID 11852051.
• Behne MJ, Meyer JW, Hanson KM, Barry NP, Murata S, Crumrine D, et al. (December 2002). "NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging". The Journal of Biological Chemistry. 277 (49): 47399–406. doi:10.1074/jbc.M204759200. PMID 12221084.