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0  structures 266  species 0  interactions 364  sequences 2  architectures

Family: Na_H_antiport_3 (PF07399)

Summary: Putative Na+/H+ antiporter

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Sodium–hydrogen antiporter 3". More...

Sodium–hydrogen antiporter 3 Edit Wikipedia article

AliasesSLC9A3, NHE3, NHE-3, Sodium–hydrogen antiporter 3, DIAR8, solute carrier family 9 member A3
External IDsOMIM: 182307 MGI: 105064 HomoloGene: 55804 GeneCards: SLC9A3
Gene location (Human)
Chromosome 5 (human)
Chr.Chromosome 5 (human)[1]
Chromosome 5 (human)
Genomic location for SLC9A3
Genomic location for SLC9A3
Band5p15.33Start470,456 bp[1]
End524,449 bp[1]
RNA expression pattern
PBB GE SLC9A3 207212 at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 5: 0.47 – 0.52 MbChr 13: 74.12 – 74.17 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Sodium–hydrogen antiporter 3 also known as sodium–hydrogen exchanger 3 (NHE3) or solute carrier family 9 member 3 (SLC9A3) is a protein that in humans is encoded by the SLC9A3 gene.[5][6]

SLC9A3 is a sodium–hydrogen antiporter. It is found on the apical side of the epithelial cells of the proximal tubule of the nephron of the kidney, in the apical membrane of enterocytes of the intestine, as well as the basolateral side of both duodenal and pancreatic cells responsible for the release of HCO−3 into the duodenal lumen. It is primarily responsible for maintaining the balance of sodium. It is also indirectly linked to buffering of blood pH. The NHE3 antiporter imports one sodium ion into the cytosol of a tubule cell as it ejects one hydrogen ion from the cell into the lumen of the proximal tubule. The sodium within the tubule cell may then be retained by the body rather than excreted in the urine. The NHE3 antiporter indirectly contributes to blood buffering capacity because hydrogen ions that are ejected are the products of the carbonic anhydrase enzyme, which also makes bicarbonate.[7]


Protein kinase C stimulates NHE3, while protein kinase A inhibits it.[8]

There is a specific protein functioning as an NHE3 regulator, Sodium-hydrogen antiporter 3 regulator 1.



  • Insulin[10] stimulates NHE3 and thereby proximal tubule sodium absorption.


Sodium–hydrogen antiporter 3 has been shown to interact with CHP.[11]


  1. ^ a b c ENSG00000066230 GRCh38: Ensembl release 89: ENSG00000281861, ENSG00000066230 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036123 - 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. ^ "Entrez Gene: SLC9A3 Solute carrier family 9 (sodium/hydrogen exchanger), member 3".
  6. ^ Brant SR, Bernstein M, Wasmuth JJ, Taylor EW, McPherson JD, Li X, Walker S, Pouyssegur J, Donowitz M, Tse CM (March 1993). "Physical and genetic mapping of a human apical epithelial Na+/H+ exchanger (NHE3) isoform to chromosome 5p15.3". Genomics. 15 (3): 668–72. doi:10.1006/geno.1993.1122. PMID 8096830.
  7. ^ VI. Mechanisms of Salt & Water Reabsorption Archived February 10, 2007, at the Wayback Machine
  8. ^ 852 Walter F., PhD. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 852
  9. ^ Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Bell N, Tabora J, Joly KM, Navre M, Jacobs JW, Charmot D (2014). "Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans". Sci Transl Med. 6 (227): 227ra36. doi:10.1126/scitranslmed.3007790. PMID 24622516.
  10. ^ Klisic J, Hu MC, Nief V, Reyes L, Fuster D, Moe OW, Ambühl PM (2002). "Insulin activates Na(+)/H(+) exchanger 3: biphasic response and glucocorticoid dependence". Am J Physiol Renal Physiol. 283 (3): 532ra539. doi:10.1152/ajprenal.00365.2001. PMID 12167605.
  11. ^ Inoue H, Nakamura Y, Nagita M, Takai T, Masuda M, Nakamura N, Kanazawa H (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.

Further reading

  • McDonough AA, Leong PK, Yang LE (2003). "Mechanisms of pressure natriuresis: how blood pressure regulates renal sodium transport". Ann. N. Y. Acad. Sci. 986: 669–77. doi:10.1111/j.1749-6632.2003.tb07281.x. PMID 12763917.
  • Orlowski J, Kandasamy RA, Shull GE (1992). "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". J. Biol. Chem. 267 (13): 9331–9. PMID 1577762.
  • Brant SR, Yun CH, Donowitz M, Tse CM (1995). "Cloning, tissue distribution, and functional analysis of the human Na+/N+ exchanger isoform, NHE3". Am. J. Physiol. 269 (1 Pt 1): C198-206. doi:10.1152/ajpcell.1995.269.1.C198. PMID 7631746.
  • Colombani V, Silviani V, Marteau C, Lerique B, Cartouzou G, Gerolami A (1996). "Presence of the NHE3 isoform of the Na+/H+ exchanger in human gallbladder". Clin. Sci. 91 (2): 209–12. doi:10.1042/cs0910209. PMID 8795445.
  • Dudeja PK, Rao DD, Syed I, Joshi V, Dahdal RY, Gardner C, Risk MC, Schmidt L, Bavishi D, Kim KE, Harig JM, Goldstein JL, Layden TJ, Ramaswamy K (1996). "Intestinal distribution of human Na+/H+ exchanger isoforms NHE-1, NHE-2, and NHE-3 mRNA". Am. J. Physiol. 271 (3 Pt 1): G483-93. PMID 8843774.
  • 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.
  • Yun CH, Lamprecht G, Forster DV, Sidor A (1998). "NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin". J. Biol. Chem. 273 (40): 25856–63. doi:10.1074/jbc.273.40.25856. PMID 9748260.
  • Biemesderfer D, Nagy T, DeGray B, Aronson PS (1999). "Specific association of megalin and the Na+/H+ exchanger isoform NHE3 in the proximal tubule". J. Biol. Chem. 274 (25): 17518–24. doi:10.1074/jbc.274.25.17518. PMID 10364184.
  • Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, O'Brien MJ, Wilkins RJ, Ellory JC, Francis MJ (1998). "Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts". Cell Biol. Int. 22 (7–8): 551–62. doi:10.1006/cbir.1998.0299. PMID 10452823.
  • Trujillo E, Alvarez de la Rosa D, Mobasheri A, González T, Canessa CM, Martín-Vasallo P (1999). "Sodium transport systems in human chondrocytes. II. Expression of ENaC, Na+/K+/2Cl- cotransporter and Na+/H+ exchangers in healthy and arthritic chondrocytes". Histol. Histopathol. 14 (4): 1023–31. PMID 10506918.
  • Repishti M, Hogan DL, Pratha V, Davydova L, Donowitz M, Tse CM, Isenberg JI (2001). "Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement". Am. J. Physiol. Gastrointest. Liver Physiol. 281 (1): G159-63. doi:10.1152/ajpgi.2001.281.1.G159. PMID 11408268.
  • Malakooti J, Memark VC, Dudeja PK, Ramaswamy K (2002). "Molecular cloning and functional analysis of the human Na(+)/H(+) exchanger NHE3 promoter". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (3): G491-500. doi:10.1152/ajpgi.00273.2001. PMID 11841999.
  • Gekle M, Serrano OK, Drumm K, Mildenberger S, Freudinger R, Gassner B, Jansen HW, Christensen EI (2002). "NHE3 serves as a molecular tool for cAMP-mediated regulation of receptor-mediated endocytosis". Am. J. Physiol. Renal Physiol. 283 (3): F549-58. doi:10.1152/ajprenal.00206.2001. PMID 12167607.
  • Kennedy DJ, Leibach FH, Ganapathy V, Thwaites DT (2002). "Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity". Pflügers Arch. 445 (1): 139–46. doi:10.1007/s00424-002-0910-1. PMID 12397398.
  • Lee SH, Seok YS, Jung HH, Oh BH, Lee HM, Kwon SY, Jung KY (2002). "Expression of mRNA transcripts of the Na+/H+ and Cl-/HCO3- exchanger isoforms in human nasal mucosa". Acta Otolaryngol. 122 (8): 866–71. doi:10.1080/003655402/000028045. PMID 12542207.
  • Inoue H, Nakamura Y, Nagita M, Takai T, Masuda M, Nakamura N, Kanazawa H (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.
  • Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nat. Biotechnol. 21 (5): 566–9. doi:10.1038/nbt810. PMID 12665801.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Putative Na+/H+ antiporter Provide feedback

This family consists of several hypothetical bacterial proteins of around 440 residues in length. The function of this family is unknown. Many members carry 11 or 12 transmembrane regions, suggesting that they might be transporters. One family member, UniProtKB:Q821X2 is classified by TCDB as being an NhaE type of Na+/H+ antiporter.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR009978

This family consists of several hypothetical bacterial proteins of around 440 residues in length. The function of this family is unknown. Many members carry 11 or 12 transmembrane regions, suggesting that they might be transporters. One family member, SWISSPROT is classified by TCDB as being an NhaE type of Na+/H+ antiporter.

Domain organisation

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Pfam Clan

This family is a member of clan IT (CL0182), which has the following description:

This superfamily of secondary carriers specific for cationic and anionic compounds, has been termed the ion transporter (IT) superfamily [1].

The clan contains the following 22 members:

ABG_transport ArsB ArsP_1 ArsP_2 CitMHS CitMHS_2 DctM DcuA_DcuB DcuC DUF1646 DUF401 EutH EXS GntP_permease Lactate_perm MatC_N Na_H_antiport_2 Na_H_antiport_3 Na_H_antiporter Na_sulph_symp NhaB SCFA_trans


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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_20945 (release 10.0)
Previous IDs: DUF1504;
Type: Family
Sequence Ontology: SO:0100021
Author: Moxon SJ
Number in seed: 33
Number in full: 364
Average length of the domain: 398.80 aa
Average identity of full alignment: 52 %
Average coverage of the sequence by the domain: 95.50 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.9 81.4
Noise cut-off 24.9 24.3
Model length: 419
Family (HMM) version: 14
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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence


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trRosetta Structure

The structural model below was generated by the Baker group with the trRosetta software using the Pfam UniProt multiple sequence alignment.

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Improved protein structure prediction using predicted inter-residue orientations. Jianyi Yang, Ivan Anishchenko, Hahnbeom Park, Zhenling Peng, Sergey Ovchinnikov, David Baker Proceedings of the National Academy of Sciences Jan 2020, 117 (3) 1496-1503; DOI: 10.1073/pnas.1914677117;