TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*2.A.36.1.1









Na+:H+ antiporter 1 (Nhe-1) (Regulated by Daxx (O35613)). An integral membrane protein that regulates intracellular pH and has a large N-terminal membrane domain of 12 transmembrane segments and an intracellular C-terminal regulatory domain (Reddy et al., 2008). The dimer catalyzes antiport with 2Na+/2H+ stoichiometry (Fuster et al., 2008). Nedd4-1 and β-arrestin-1 are key regulators of Na+/H+ exchanger 1 ubiquitylation, endocytosis and function (Simonin and Fuster et al., 2010). Important in heart disease and cancer. Structural studies have been performed using NMR (Lee et al., 2011).

Eukaryota
Metazoa
Nhe-1 of Rattus norvegicus
*2.A.36.1.2









Na+:H+ antiporter 3 (NHE-3 or NHE3). Regulated by Na+/H+ exchange regulatory cofactors (NHERF; O14745; TC #8.A.24.1.1) (Seidler et al., 2009). Cyclic AMP-mediated endocytosis of intestinal epithelial NHE3 requires binding to synaptotagmin 1 (Musch et al., 2010).  Decreased activity is responsible for congenital Na+ diarrhea in the human brush boarder (Janecke et al. 2015). Reduced functional expression of NHE3, and DRA contribute to Cl- and Na+ stool loss in microvillus inclusion disease (MVID) diarrhea (Kravtsov et al. 2016).

Eukaryota
Metazoa
Nhe-3 of Rattus norvegicus
*2.A.36.1.3









Na+/K+:H+ antiporter, Nhe-7, present in the Golgi apparatus and endosomes. There are four isoforms, NHE6-9. They regulate the luminal pH as well as intracellular trafficking, and function in cell polarity development (Ohgaki et al., 2011). Nhe-6 (Nhe6) is associated with X-linked intellectural disability and autism when processing and trafficking is impaired (Ilie et al. 2013).

Eukaryota
Metazoa
SLC9A7 of Homo sapiens
*2.A.36.1.4









Cl--dependent Na+:H+ antiporter (Nhe) (residues 1-375 are identical to Nhe-1 [TC #2.A.36.1.1]).
Eukaryota
Metazoa
Nhe of Rattus norvegicus
*2.A.36.1.5









Na+/K+:H+ antiporter, NHX2
Eukaryota
Viridiplantae
NHX2 of Lycopersicon esculentum (CAC83608)
*2.A.36.1.6









Zebrafish Na+:H+ antiporter NheC (Yan et al., 2007) (most similar to TC# 2.A.36.1.2, 48% identical)
Eukaryota
Metazoa
NheC of Danio rerio (A3KPJ8)
*2.A.36.1.7









The basolateral intestinal Na+/H+ antiporter PBO-4 (Beg et al., 2008)
Eukaryota
Metazoa
PBO-4 of Caenorhabditis elegans (Q21386)
*2.A.36.1.8









Na+/H+ exchanger, Nhx-2 (Pfeiffer et al., 2008)
Eukaryota
Metazoa
Nhx-2 of Caenorhabditis elegans (Q09432)
*2.A.36.1.9









Human Na+/H+ Exchanger, NHE-8 or SLC9A8. Functions in intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia.

Eukaryota
Metazoa
SLC9A8 of Homo sapiens
*2.A.36.1.10









Basal membrane Nhe3
Eukaryota
Metazoa
Nhe3 of Aedes aegypti (Q17L17)
*2.A.36.1.11









The Na+:H+ Exchanger, NHE1, is developmentally regulated and necessary for cell polarity (Patel and Barber, 2005).

Eukaryota
Dictyosteliida
NHE1 of Dictyostelium discoideum (Q552S0)
*2.A.36.1.12









Na+:H+ antiporter; (vacuolar/endosomal Na+  tolerance protein)

Eukaryota
Fungi
NHX1 (YDR456w) of Saccharomyces cerevisiae
*2.A.36.1.13









Na /H exchanger-1 (NHE1).  Stoichiometry = 1:1. TMS VI of NHE1 is a discontinuous pore-lining helix with residues Asn(227), Ile(233), and Leu(243) lining the translocation pore (Tzeng et al., 2010). (orthologous to NHE1 of rat, TC# 2.A.36.1.1). It regulates internal pH in human monocytes and is important in heart disease and cancer (Tsai et al. 2015). Structural studies have been performed using NMR and EPR (Lee et al., 2011; Nygaard et al. 2011).  Extracytoplasmic loops contribute to ion coordination and inhibitor sensitivity (Lee et al. 2012).  The regulation of NHE1 has been reviewed (Wakabayashi et al. 2013).  CD44 (LHR, MDU2, MDU3, MIC4; P16070) regulates breast cancer metastasis by regulating NHE1 expression (Chang et al. 2014).  The role of NHE1 in kidney proximal tubule functions, including pH regulation, vectorial Na+ transport, cell volume control and cell survival has been reviewed (Parker et al. 2015).  Helix M9 and the adjacent exofacial re-entrant loop 5 between M9 and M10 (EL5) are important elements involved in cation transport and inhibitor sensitivity (Jinadasa et al. 2015).  A 12 TMS topology has been confirmed (Liu et al. 2015).  Mutations  cause Lichtenstein-Knorr syndrome, an autosomal recessive condition that associates sensorineural hearing loss with cerebellar ataxia (Guissart et al. 2015). Cleaved FAS ligand (transmembrane CD95L; 1 TMS; P48023) activates NHE1 through the Akt/ROCK1 signalling pathway to stimulate cell motility (Monet et al. 2016).

Eukaryota
Metazoa
SLC9A1 of Homo sapiens
*2.A.36.1.14









Sodium/hydrogen exchanger 6 (Na+/H+ exchanger 6) (NHE-6) (Solute carrier family 9 member 6).  This Na+/H+ exchanger is encoded by an X-linked gene that is widely expressed and especially abundant in brain, heart and skeletal muscle where it is implicated in endosomal pH homeostasis and trafficking as well as maintenance of cell polarity. Several mutations in the coding region of NHE6 are linked with severe intellectual disability, autistic behavior, ataxia and other abnormalities (Ilie et al. 2014).  A christianson syndrome-linked mutation disrupts endosomal function and elicits neurodegeneration and cell death (Ilie et al. 2016).  Heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males (Sikora et al. 2016).

Eukaryota
Metazoa
SLC9A6 of Homo sapiens
*2.A.36.1.15









Sodium/hydrogen exchanger 3 (Na(+)/H(+) exchanger 3) (NHE-3) (Solute carrier family 9 member 3)
Eukaryota
Metazoa
SLC9A3 of Homo sapiens
*2.A.36.1.16









Sodium/hydrogen exchanger 5 (Na(+)/H(+) exchanger 5) (NHE-5) (Solute carrier family 9 member 5)
Eukaryota
Metazoa
SLC9A5 of Homo sapiens
*2.A.36.1.17









Sodium/hydrogen exchanger 2 (Na+/H+ exchanger 2) (NHE-2 or NHE2) (Solute carrier family 9 member 2).  Mediates butyrate-dependent Na+ absorption (Rajendran et al. 2015).

Eukaryota
Metazoa
SLC9A2 of Homo sapiens
*2.A.36.1.18









Sodium/hydrogen exchanger 4 (Na(+)/H(+) exchanger 4) (NHE-4) (Solute carrier family 9 member 4)
Eukaryota
Metazoa
SLC9A4 of Homo sapiens
*2.A.36.1.19









Sodium/hydrogen exchanger 9 (Na(+)/H(+) exchanger 9) (NHE-9) (Solute carrier family 9 member 9)
Eukaryota
Metazoa
SLC9A9 of Homo sapiens
*2.A.36.1.20









Endomembrane (Golgi) K+, Na+/H+ exchanger 5, NHX5, of 521 aas and 11 TMSs.  Three acidic residues are critical for transport activity as well as seedling growth, regulation of protein transport into vesicles and ionic homeostasis (Qiu 2016). NHX6 is 80% identical to NHX5 (535 aas and 11 TMSs) and serves the same function.

Eukaryota
Viridiplantae
NHX5 of Arabidopsis thaliana (Q9SLJ7)
*2.A.36.1.21









Sodium:proton antiporter of 468 aas and 13 TMSs, Sod2 or NHE1.  Residues within TMS 11 play important roles in transport, suggesting that this TMS forms part of the ion translocation core (Dutta et al. 2017).

Eukaryota
Fungi
NHE1 of Schizosaccharomyces pombe (Fission yeast)
*2.A.36.2.1









Putative Na+/H+ exchanger, Cpa1 (399aas; 13 TMSs)

Archaea
Euryarchaeota
Cpa1 of Methanothermobacter thermautotrophicus (O26854)
*2.A.36.2.2









The Na+/Li+:H+ antiporter, Nha2. Also catalyzes Na+:Li+ antiport; contributes to salt homeostasis; correlates with heritable hypertension (Xiang et al., 2007).
Eukaryota
Metazoa
SLC9B2 of Homo sapiens
*2.A.36.2.3









solute carrier family 9, subfamily B (NHA1, cation proton antiporter 1), member 1
Eukaryota
Metazoa
SLC9B1 of Homo sapiens
*2.A.36.3.1









Putative antiporter of 549 aas (function unknown) (Verkhovskaya et al. 2001).

Bacteria
Proteobacteria
YjcE of E. coli
*2.A.36.3.2









Na+, K+, Li+, Rb+:H+ antiporter, YvgP
Bacteria
Firmicutes
YvgP of Bacillus subtilis (CAB15347)
*2.A.36.3.3









Uncharacterized Na(+)/H(+) exchanger Rv2287/MT2345
Bacteria
Actinobacteria
Rv2287 of Mycobacterium tuberculosis
*2.A.36.4.1









[Na+ or K+]:H+ antiporter Nha1
Eukaryota
Fungi
Nha1 (YLR138w) of Saccharomyces cerevisiae
*2.A.36.4.2









Na+:H+ antiporter, Nha2 or Sod2-22.  Exports Na+ and Li+ but not K+.  Three residues, T141 in TMS 4, A179 in TMS 5 and V375 in TMS 11, determine the cation selectivity (Kinclova-Zimmermannova et al. 2015).

Eukaryota
Fungi
Nha2 of Zygosaccharomyces rouxii
*2.A.36.4.3









Na+:H+ antiporter, Nha1 or Sod1.  It provides salt tolerance by removing sodium or lithium ions in exchange for protons, and TMS 4 plays an important role (Ullah et al. 2013).

Eukaryota
Fungi
Nha1 of Schizosaccharomyces pombe
*2.A.36.4.4









The K+, Rb+ and other alkali metal cation efflux porter, Cnh1 (Kinclova-Zimmermannova and Sychrova, 2007). Transports Na+, K+, Li+ and Rb+ in several Candida species.  Confers tolerance to high salt concentrations (Krauke and Sychrova 2008).
Eukaryota
Fungi
Cnh1 of Candida albicans (Q9P937)
*2.A.36.4.5









Probable Na(+)/H(+) antiporter C3A11.09
Eukaryota
Fungi
SPAC3A11.09 of Schizosaccharomyces pombe
*2.A.36.5.1









Low-affinity Na+ (K+, Li+ or Cs+):H+ antiporter, Nhx1
Eukaryota
Viridiplantae
Nhx1 of Arabidopsis thaliana
*2.A.36.5.2









Vacuolar Na+/H+ antiporter, NHX1. A class-I type NHX. Confers NaCl tolerance and therefore pumps Na+ from the cytosol to the vacuole (Jha et al., 2011).

Eukaryota
Viridiplantae
NHX1 of Salicornia brachiata (B1PLB6)
*2.A.36.5.3









Vacuolar Na+/H+ exchanger, DgNHX1 or NHX1, of 510 aas and 13 putative (but possibly 9 actual) TMSs. Involved in adaptation to salt stress conditions and expressed under these same conditions (Liu et al. 2013). 

Eukaryota
Viridiplantae
NHX1 of Chrysanthemum morifolium (Florist's daisy) (Dendranthema grandiflorum)
*2.A.36.5.4









Vacuorlar Na+/H+ exchanger, Nhx1 of 542 aas and 13 TMSs.  Involved in salt tolerance (Mishra et al. 2014).

Eukaryota
Viridiplantae
Nhx1 of Vigna radiata (Mung bean)
*2.A.36.5.5









Na+:H+ antiporter, Nhx1 of 470 aas and 9 TMSs. NHX1 can confer a high level of salinity tolerance when overexpressed in Brassica juncea. Verma et al. 2007 reported its functional characterization. Overexpression conferred a high level of salinity tolerance in rice. Transgenic rice plants overexpressing PgNHX1 developed more extensive root systems and completed their life cycle by setting flowers and seeds in the presence of 150 mM NaCl.

Eukaryota
Viridiplantae
Nhx1 of Pennisetum americanum (Pearl millet) (Pennisetum glaucum)
*2.A.36.6.1









Putative Na+:H+ antiporter, Nhe2
Archaea
Euryarchaeota
The AF0846 gene (Nhe2) of Archaeoglobus fulgidus
*2.A.36.6.2









Na+ (Li+):H+ antiporter NhaG (Gouda et al. 2001).  Several very similar antiporters have been isolated from uncultured bacteria from a lake in China (Wang et al. 2013).

Bacteria
Firmicutes
NhaG of Bacillus subtilis ATCC9372
*2.A.36.6.3









K+:H+ antiporter, KhaP2 (NhaP2). Participates in volume control under low osmorality conditions (Radchenko et al., 2006; Resch et al., 2010)

Bacteria
Proteobacteria
KhaP2 of Vibrio parahaemolyticus (Q87KV8)
*2.A.36.6.4









The K+(NH4+):H+ antiporter, NhaP (confers alkali resistance for alkaline pH homeostasis) (Wei et al., 2007)
Bacteria
Proteobacteria
NhaP of Alkalimonas amylolytica (Q0ZAH6)
*2.A.36.6.5









K+:H+ antiporter NhaP2 (catalyzes K+:H+ and possibly K+:Li+ exchange; Resch et al., 2010). (84% identical to 2.A.36.6.3)

Bacteria
Proteobacteria
NhaP2 of Vibrio cholerae (Q9KNM9)
*2.A.36.6.6









Na+/H+ antiporter 1 (MjNhaP1).  NhaP1 is a dimer with 13 TMSs per monomer as revealed by electron crystalography of 2-d crystals (Goswami et al. 2011).  This structure is contrasted with that of the distantly related bacterial NhaA; these two structures are quite different in detail, but similar within the 6 TMS repeat unit. Asp234/235 of helix VIII are involved in ligand-binding, and helix X plays a role in the activation of the transporter (Kedrov et al. 2007).

Archaea
Euryarchaeota
MJ0057 (NhaP1) of Methanocaldococcus jannaschii
*2.A.36.6.7









NhaH Na+/Li+/H+ antiporter (Yang et al. 2006).

Bacteria
Firmicutes
NhaH of Halobacillus dabanensis (Q2XWL3)
*2.A.36.6.8









Na+/H+ antiporter of 424 aas, NhaP, that extrudes sodium in exchange for external protons. Has weak (if any) Li+/H+ antiport activity (Kuroda et al. 2004).

Bacteria
Proteobacteria
NhaP of Pseudomonas aeruginosa
*2.A.36.6.9









Na+/H+ antiporter, NhaP, of 443 aas.  Several 3-d structures are known (Wöhlert et al. 2014).  The ion is coordinated by three acidic side chains, a water molecule, a serine and a main-chain carbonyl in an unwound stretch of TMS 5 at the deepest point of a negatively charged cytoplasmic funnel. A second narrow polar channel may facilitate proton uptake from the cytoplasm. Transport activity is cooperative at pH 6 but not at pH 5, due to pH-dependent allosteric coupling of protomers through two histidines at the dimer interface (Wöhlert et al. 2014).

Archaea
Euryarchaeota
NhaP of Pyrococcus abyssi
*2.A.36.6.10









Na+/H+ antiporter of 403 aas and 11 predicted TMSs, NhaH. Exchanges Na+ or Li+ but not K+ for H+ (Zou et al. 2008).  Confers Na+ and Li+ tolerance.

Bacteria
Firmicutes
NhaH of Halobacillus aidingensis
*2.A.36.6.11









Na+/H+ antiporter, NhaP2 (YcgO; CvrA) of 578 aas and 13 TMSs. Involved in growth at low osmolarity, intracellular K+ maintenance, and volume regulation (Verkhovskaya et al. 2001).

Bacteria
Proteobacteria
NhaP2 of E. coli
*2.A.36.7.1









ApNhaP: a Na+:H+ antiporter at pH 5-9; a Ca2+:H+ antiporter at alkaline pH (not an Li:H+ antiporter) (Waditee et al. 2001).  When the gene for ApNhaP is expressed in the fresh water cyanobacterium, Synechococcus sp. PCC 7942, it became salt tolerant and could live in salt water (Waditee et al. 2002; ).

Bacteria
Cyanobacteria
ApNhaP of Aphanothece halophytica
*2.A.36.7.2









Low affinity (Km=8 mM) Na+(Li+):H+ antiporter, NhaS1
Bacteria
Cyanobacteria
NhaS1 of Synechocystis sp. PCC6803
*2.A.36.7.3









Li+/H+ antiporter, AtNHX8 (An et al., 2007).  An orthologue in Puccinellia tenuiflora (alkali grass) is up regulated under salt stress and confers tolerance to high NaCl stress (Wang et al. 2011).

Eukaryota
Viridiplantae
NHX8 of Arabidopsis thaliana (Q3YL57)
*2.A.36.7.4









Sodium/hydrogen exchanger 11 (Na(+)/H(+) exchanger 11) (NHE-11) (Solute carrier family 9 member 11) (Solute carrier family 9 member C2)
Eukaryota
Metazoa
SLC9C2 of Homo sapiens
*2.A.36.7.5









Sodium/hydrogen exchanger 10 (Na( )/H( ) exchanger 10) (NHE-10) (Solute carrier family 9 member 10) (Solute carrier family 9 member C1) (Sperm-specific Na( )/H( ) exchanger) (sNHE).  Predicted to have 17 TMSs in a 13 4 TMS arrangement.  The last 4 TMSs are homologous to the 4 TMS voltage sensor of the Ca2 channel, 1.A.1.11.7.

Eukaryota
Metazoa
SLC9C1 of Homo sapiens
*2.A.36.7.6









Dimeric Salt-Overly-Sensitive 1 (SOS1) sodium:proton exchanger 7 (NHX7) (Núñez-Ramírez et al. 2012).  The salt stress-induced SALT-OVERLY-SENSITIVE (SOS) pathway in Arabidopsis thaliana involves the perception of a calcium signal by the SOS3 and SOS3-like CALCIUM-BINDING PROTEIN8 (SCaBP8; 5.b.1.1.8) calcium sensors, which then interact with and activate the SOS2 protein kinase (9.B.106.3.4), forming a complex at the plasma membrane that activates the SOS1 Na⁺/H⁺ exchanger (Lin et al. 2014).  The involvement of SOS1 in Na+ efflux in plant roots has been reviewed (Britto and Kronzucker 2015). SOS1 appears to encode a salinity-inducible plasma membrane Na+ /H+ antiporter (Song et al. 2012).

 

Eukaryota
Viridiplantae
SOS1 of Arabidopsis thaliana
*2.A.36.7.7









Testis-specific sodium:proton exchanger, mtsNHE (Slc9c1) of 1175 aas and 12 - 16 TMSs.  It is present in sperm flagellae and seems to be required for optimal sperm motility, fertilization and the acrosome reaction (Liu et al. 2010).  69% identical to the human NHE, TC# 2.A.36.7.5.  It may have a 12 TMS topology, but has a long C-terminal hydrophilic domain with a segment showing 2 - 4 TMSs. 

Eukaryota
Metazoa
mtsNHE of Mus musculus
*2.A.36.7.8









Putative Na+/H+ antiporter of 1142 aas

Nha of Eimeria tenella (Coccidian parasite)
*2.A.36.7.9









Sodium/proton antiporter, Nhe1 of 1690 aas

Eukaryota
Apicomplexa
Nhe1 of Plasmodium falciparum
*2.A.36.7.10









Na+/H+ antiporter of 1145 aas and 12 TMSs, SOS1.  Suppresses salt (200 mM NaCl) sensitivity, promoting tolerance (Wu et al. 2007). 65% identical to the A. thaliana homologue (TC# 2.A.36.7.6)

Eukaryota
Viridiplantae
SOS1 of Populus euphratica (Euphrates poplar)