Sodium–hydrogen antiporter 1

Solute carrier family 9, subfamily A (NHE1, cation proton antiporter 1), member 1

PDB rendering based on 2bec.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1Y4E, 2BEC, 2E30, 2HTG, 2KBV, 2L0E, 2MDF, 2YGG

Identifiers

Symbols

SLC9A1 ; APNH; LIKNS; NHE-1; NHE1; PPP1R143

External IDs

OMIM: 107310 MGI: 102462 HomoloGene: 20660 ChEMBL: 2781 GeneCards: SLC9A1 Gene

Gene ontology
Molecular function	• protein binding • calmodulin binding • phosphatidylinositol-4,5-bisphosphate binding • solute:proton antiporter activity • sodium:proton antiporter activity • protein phosphatase 2B binding • protein binding, bridging • protein complex scaffold • calcium-dependent protein binding • sodium:proton antiporter activity involved in regulation of cardiac muscle cell membrane potential
Cellular component	• nucleoplasm • cytoplasm • mitochondrion • endoplasmic reticulum • endoplasmic reticulum membrane • plasma membrane • integral component of plasma membrane • focal adhesion • cell surface • intercalated disc • integral component of membrane • basolateral plasma membrane • apical plasma membrane • lamellipodium • T-tubule • membrane raft • perinuclear region of cytoplasm • extracellular exosome • cation-transporting ATPase complex
Biological process	• carbohydrate metabolic process • ion transport • cellular sodium ion homeostasis • regulation of pH • response to acidic pH • positive regulation of cardiac muscle hypertrophy • regulation of cardiac muscle contraction by calcium ion signaling • cell growth • cell migration • maintenance of cell polarity • glycosaminoglycan metabolic process • hyaluronan metabolic process • hyaluronan catabolic process • positive regulation of cell growth • cellular response to insulin stimulus • positive regulation of mitochondrial membrane permeability • response to muscle stretch • response to drug • positive regulation of apoptotic process • negative regulation of apoptotic process • small molecule metabolic process • positive regulation of action potential • positive regulation of transcription from RNA polymerase II promoter • protein oligomerization • regulation of intracellular pH • regulation of stress fiber assembly • positive regulation of NFAT protein import into nucleus • regulation of focal adhesion assembly • regulation of sensory perception of pain • cardiac muscle cell differentiation • transmembrane transport • positive regulation of calcineurin-NFAT signaling cascade • neuron death • cellular response to antibiotic • cellular response to electrical stimulus • cellular response to mechanical stimulus • sodium ion export • cellular response to hypoxia • cellular response to acidic pH • cellular response to epinephrine stimulus • cardiac muscle cell contraction • regulation of cardiac muscle cell membrane potential • regulation of the force of heart contraction by cardiac conduction • sodium ion import across plasma membrane • positive regulation of the force of heart contraction • hydrogen ion transmembrane transport • positive regulation of calcium:sodium antiporter activity
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 1:
27.1 – 27.17 Mb

Chr 4:
133.37 – 133.42 Mb

PubMed search

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]

References

↑ Fliegel L, Dyck JR, Wang H, Fong C, Haworth RS (August 1993). "Cloning and analysis of the human myocardial Na+/H+ exchanger". Mol. Cell. Biochem. 125 (2): 137–43. doi:10.1007/BF00936442. PMID 8283968.
↑ Mattei MG, Sardet C, Franchi A, Pouysségur J (1988). "The human amiloride-sensitive Na+/H+ antiporter: localization to chromosome 1 by in situ hybridization". Cytogenet. Cell Genet. 48 (1): 6–8. doi:10.1159/000132575. PMID 2846238.
↑ 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". J. Biol. Chem. 277 (39): 36085–91. doi:10.1074/jbc.M111952200. PMID 12138085.
↑ 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". Biol. Pharm. Bull. 26 (2): 148–55. doi:10.1248/bpb.26.148. PMID 12576672.
↑ Lin X, Barber DL (October 1996). "A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange". Proc. Natl. Acad. Sci. U.S.A. 93 (22): 12631–6. doi:10.1073/pnas.93.22.12631. PMC 38044. PMID 8901634.
↑ Pang T, Su X, Wakabayashi S, Shigekawa M (May 2001). "Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers". J. Biol. Chem. 276 (20): 17367–72. doi:10.1074/jbc.M100296200. PMID 11350981.
↑ Spreitzer, Helmut (26 May 2015). "Rimeporide". Österreichische Apothekerzeitung (in German) 69 (11): 12.

Yu L, Quinn DA, Garg HG, Hales CA (June 2008). "Deficiency of the NHE1 gene prevents hypoxia-induced pulmonary hypertension and vascular remodeling". Am. J. Respir. Crit. Care Med. 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". Am. J. Physiol. Lung Cell Mol. Physiol. 289 (5): L867–74. doi:10.1152/ajplung.00455.2004. PMID 15964895.
Cingolani HE, Ennis IL (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 (2007). "Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1". Curr. Opin. Nephrol. Hypertens. 16 (4): 365–72. doi:10.1097/MNH.0b013e3281bd888d. PMID 17565280.
Tse CM, Ma AI, Yang VW, Watson AJ, Levine S, Montrose MH, Potter J, Sardet C, Pouyssegur J, Donowitz M (1991). "Molecular cloning and expression of a cDNA encoding the rabbit ileal villus cell basolateral membrane Na+/H+ exchanger". EMBO J. 10 (8): 1957–67. PMC 452875. PMID 1712287.
Dudley CR, Giuffra LA, Tippett P, Kidd KK, Reeders ST (1990). "The Na+/H+ antiporter: a "melt" polymorphism allows regional mapping to the short arm of chromosome 1". Hum. Genet. 86 (1): 79–83. doi:10.1007/bf00205179. PMID 1979310.
Sardet C, Counillon L, Franchi A, Pouysségur J (1990). "Growth factors induce phosphorylation of the Na+/H+ antiporter, glycoprotein of 110 kD". Science 247 (4943): 723–6. doi:10.1126/science.2154036. PMID 2154036.
Sardet C, Franchi A, Pouysségur J (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". Cytogenet. Cell Genet. 48 (1): 6–8. doi:10.1159/000132575. PMID 2846238.
Counillon L, Pouysségur J, Reithmeier RA (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 (1993). "Cloning and analysis of the human myocardial Na+/H+ exchanger". Mol. Cell. Biochem. 125 (2): 137–43. doi:10.1007/BF00936442. PMID 8283968.
Lin X, Barber DL (1996). "A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange". Proc. Natl. Acad. Sci. U.S.A. 93 (22): 12631–6. doi:10.1073/pnas.93.22.12631. PMC 38044. PMID 8901634.
Shrode LD, Gan BS, D'Souza SJ, Orlowski J, Grinstein S (1998). "Topological analysis of NHE1, the ubiquitous Na+/H+ exchanger using chymotryptic cleavage". Am. J. Physiol. 275 (2 Pt 1): C431–9. PMID 9688597.
Wakabayashi S, Pang T, Su X, Shigekawa M (2000). "A novel topology model of the human Na(+)/H(+) exchanger isoform 1". J. Biol. Chem. 275 (11): 7942–9. doi:10.1074/jbc.275.11.7942. PMID 10713111.
Garden OA, Musk P, Worthington-White DA, Dewey MJ, Rich IN (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 Genet. Cytogenet. 120 (1): 37–43. doi:10.1016/S0165-4608(99)00246-0. PMID 10913675.
Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL (2000). "Direct binding of the Na--H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation". Mol. Cell 6 (6): 1425–36. doi:10.1016/S1097-2765(00)00139-8. PMID 11163215.
Lehoux S, Florian JA, Berk BC (2001). "14-3-3 Binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange". J. Biol. Chem. 276 (19): 15794–800. doi:10.1074/jbc.M100410200. PMID 11279064.
Pang T, Su X, Wakabayashi S, Shigekawa M (2001). "Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers". J. Biol. Chem. 276 (20): 17367–72. doi:10.1074/jbc.M100296200. PMID 11350981.
Yan W, Nehrke K, Choi J, Barber DL (2001). "The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor". J. Biol. Chem. 276 (33): 31349–56. doi:10.1074/jbc.M102679200. PMID 11369779.
Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, Fisher RJ, Fliegel L, Durum SK (2001). "Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization". Mol. Cell. Biol. 21 (22): 7545–57. doi:10.1128/MCB.21.22.7545-7557.2001. PMC 99926. PMID 11604491.
Mailänder J, Müller-Esterl W, Dedio J (2001). "Human homolog of mouse tescalcin associates with Na(+)/H(+) exchanger type-1". FEBS Lett. 507 (3): 331–5. doi:10.1016/S0014-5793(01)02986-6. PMID 11696366.
Shen MR, Wilkins RJ, Chou CY, Ellory JC (2002). "Anion exchanger isoform 2 operates in parallel with Na(+)/H(+) exchanger isoform 1 during regulatory volume decrease of human cervical cancer cells". FEBS Lett. 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, Clegg RW, Gratton E, Holleran WM, Elias PM, Mauro TM (2002). "NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging". J. Biol. Chem. 277 (49): 47399–406. doi:10.1074/jbc.M204759200. PMID 12221084.

PDB gallery

2bec: Crystal structure of CHP2 in complex with its binding region in NHE1 and insights into the mechanism of pH regulation

2e30: Solution structure of the cytoplasmic region of Na+/H+ exchanger 1 complexed with essential cofactor calcineurin B homologous protein 1

Membrane proteins, carrier proteins: membrane transport proteins solute carrier (TC 2A)

By group

SLC1–10

(1):	high affinity glutamate and neutral amino-acid transporter SLC1A1 2 3 4 5 6 7

(2):	facilitative GLUT transporter SLC2A1 2 3 4 5 6 7 8 9 10 11 12 13 14

(3):	heavy subunits of heterodimeric amino-acid transporters SLC3A1 2

(4):	bicarbonate transporter SLC4A1 2 3 4 5 6 7 8 9 10 11

(5):	sodium glucose cotransporter SLC5A1 2 3 4 5 6 7 8 9 10 11 12

(6):	sodium- and chloride- dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A20

(7):	cationic amino-acid transporter/glycoprotein-associated SLC7A1 SLC7A2 SLC7A3 SLC7A4 glycoprotein-associated/light or catalytic subunits of heterodimeric amino-acid transporters SLC7A5 SLC7A6 SLC7A7 SLC7A8 SLC7A9 SLC7A10 SLC7A11 SLC7A13 SLC7A14

(8):	Na+/Ca2+ exchanger SLC8A1 SLC8A2 SLC8A3

(9):	Na+/H+ exchanger SLC9A1 SLC9A2 SLC9A3 SLC9A4 SLC9A5 SLC9A6 SLC9A7 SLC9A8 SLC9A9 SLC9A10 SLC9A11

(10):	sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 10A1 10A2 10A3 10A7

SLC11–20

(11):	proton coupled metal ion transporter SLC11A1 SLC11A2 11A3

(12):	electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9

(13):	human Na+-sulfate/carboxylate cotransporter SLC13A1 SLC13A2 SLC13A3 SLC13A4 SLC13A5

(14):	urea transporter SLC14A1 SLC14A2

(15):	proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4

(16):	monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A14

(17):	Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9

(18):	vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3

(19):	folate/thiamine transporter SLC19A1 SLC19A2 SLC19A3

(20):	type III Na+-phosphate cotransporter SLC20A1 SLC20A2

SLC21–30

(21):	Organic anion-transporting polypeptide SLCO1A2 SLCO1B1 SLCO1B3 SLCO1B4 SLCO1C1 SLCO2A1 SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1(SLCO6A1)

(22):	organic cation/anion/zwitterion transporter SLC22A1 SLC22A2 SLC22A3 SLC22A4 SLC22A5 SLC22A6 SLC22A7 SLC22A8 SLC22A9 SLC22A10 SLC22A11 SLC22A12 SLC22A13 SLC22A14 SLC22A15 SLC22A16 SLC22A17 SLC22A18 SLC22A19 SLC22A20

(23):	Na+-dependent ascorbic acid transporter SLC23A1 SLC23A2 SLC23A3 SLC23A4

(24):	Na+/(Ca2+-K+) exchanger SLC24A1 SLC24A2 SLC24A3 SLC24A4 SLC24A5 SLC24A6

(25):	mitochondrial carrier SLC25A1 SLC25A2 SLC25A3 SLC25A4 SLC25A5 SLC25A6 SLC25A7 SLC25A8 SLC25A9 SLC25A10 SLC25A11 SLC25A12 SLC25A13 SLC25A14 SLC25A15 SLC25A16 SLC25A17 SLC25A18 SLC25A19 SLC25A20 SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25 SLC25A26 SLC25A27 SLC25A28 SLC25A29 SLC25A30 SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35 SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A40 SLC25A41 SLC25A42 SLC25A43 SLC25A44 SLC25A45 SLC25A46

(26):	multifunctional anion exchanger SLC26A1 SLC26A2 SLC26A3 SLC26A4 SLC26A5 SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC26A10 SLC26A11

(27):	fatty acid transport proteins SLC27A1 SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6

(28):	Na+-coupled nucleoside transport (SLC28A1 SLC28A2 SLC28A3

(29):	facilitative nucleoside transporter SLC29A1 SLC29A2 SLC29A3 SLC29A4

(30):	zinc efflux SLC30A1 SLC30A2 SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7 SLC30A8 SLC30A9 SLC30A10

SLC31–40

(31):	copper transporter SLC31A1

(32):	Vesicular glutamate transporter 1 SLC32A1

(33):	Acetyl-CoA transporter SLC33A1

(34):	type II Na+-phosphate cotransporter SLC34A1 SLC34A2 SLC34A3

(35):	nucleoside-sugar transporter SLC35A1 SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1 SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2 SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2 SLC35E3 SLC35E4

(36):	proton-coupled amino-acid transporter SLC36A1 SLC36A2 SLC36A3 SLC36A436A2

(37):	sugar-phosphate/phosphate exchanger SLC37A1 SLC37A2 SLC37A3 SLC37A4

(38):	System A & N, sodium-coupled neutral amino-acid transporter SLC38A1 SLC38A2 SLC38A3 SLC38A4 SLC38A5 SLC38A6 SLC38A10

(39):	metal ion transporter SLC39A1 SLC39A2 SLC39A3 SLC39A4 SLC39A5 SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC39A10 SLC39A11 SLC39A12 SLC39A13 SLC39A14

(40):	basolateral iron transporter SLC40A1

SLC41–48

(41):	Magnesium transporter E SLC41A1 SLC41A2 SLC41A3

(42):	Ammonia transporter RhAG RhBG RhCG

(43):	Na+-independent, system-L like amino-acid transporter SLC43A1 SLC43A2 SLC43A3

(44):	Choline-like transporter SLC44A1 SLC44A2 SLC44A3 SLC44A4 SLC44A5

(45):	Putative sugar transporter SLC45A1 SLC45A2 SLC54A3 SLC45A4

(46):	Folate transporter SLC46A1 SLC46A2

(47):	multidrug and toxin extrusion SLC47A1 SLC47A2

(48):	Heme transporter

SLCO1–4

O1A2 O1B1 O1B3 O2B1 O431 O4A1

Ion pumps

Symporter, Cotransporter	Na+/K+,l- Na/Pi3 Na+/Cl- Na/glucose Na+/I- Cl-/K+ 4 5

Antiporter (exchanger)	Na+/H+ Na+/Ca2+ Na+/(Ca2+-K+) - Cl-/HCO3- (Band 3) Cl-formate exchanger Cl-oxalate exchanger

see also solute carrier disorders

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Sodium–hydrogen antiporter 1

Function

Interactions

References

Further reading