Sodium–hydrogen antiporter 3 explained

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.^{[1] [2]}

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.^[3]

Regulation

Protein kinase C stimulates NHE3, while protein kinase A inhibits it.^[4]

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

Inhibitors

• Tenapanor^[5]

Stimulators

• Insulin^[6] stimulates NHE3 and thereby proximal tubule sodium absorption.

Interactions

Sodium–hydrogen antiporter 3 has been shown to interact with CHP.^[7]

Further reading

• McDonough AA, Leong PK, Yang LE . Mechanisms of pressure natriuresis: how blood pressure regulates renal sodium transport . Ann. N. Y. Acad. Sci. . 986 . 669–77 . 2003 . 12763917 . 10.1111/j.1749-6632.2003.tb07281.x . 86115595 .
• Orlowski J, Kandasamy RA, Shull GE . 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 . 1992 . 10.1016/S0021-9258(19)50428-8 . 1577762 . free .
• Brant SR, Yun CH, Donowitz M, Tse CM . Cloning, tissue distribution, and functional analysis of the human Na+/N+ exchanger isoform, NHE3 . Am. J. Physiol. . 269 . 1 Pt 1 . C198-206 . 1995 . 7631746 . 10.1152/ajpcell.1995.269.1.C198.
• Colombani V, Silviani V, Marteau C, Lerique B, Cartouzou G, Gerolami A . Presence of the NHE3 isoform of the Na+/H+ exchanger in human gallbladder . Clin. Sci. . 91 . 2 . 209–12 . 1996 . 8795445 . 10.1042/cs0910209.
• 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 . 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 . 1996 . 8843774 . 10.1152/ajpgi.1996.271.3.G483.
• Lin X, Barber DL . A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange . Proc. Natl. Acad. Sci. U.S.A. . 93 . 22 . 12631–6 . 1996 . 8901634 . 38044 . 10.1073/pnas.93.22.12631 . 1996PNAS...9312631L . free .
• Yun CH, Lamprecht G, Forster DV, Sidor A . 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 . 1998 . 9748260 . 10.1074/jbc.273.40.25856 . free .
• Biemesderfer D, Nagy T, DeGray B, Aronson PS . Specific association of megalin and the Na+/H+ exchanger isoform NHE3 in the proximal tubule . J. Biol. Chem. . 274 . 25 . 17518–24 . 1999 . 10364184 . 10.1074/jbc.274.25.17518 . free .
• Mobasheri A, Golding S, Pagakis SN, Corkey K, Pocock AE, Fermor B, O'Brien MJ, Wilkins RJ, Ellory JC, Francis MJ . Expression of cation exchanger NHE and anion exchanger AE isoforms in primary human bone-derived osteoblasts . Cell Biol. Int. . 22 . 7–8 . 551–62 . 1998 . 10452823 . 10.1006/cbir.1998.0299 . 12201584 .
• Trujillo E, Alvarez de la Rosa D, Mobasheri A, González T, Canessa CM, Martín-Vasallo P . 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 . 1999 . 10506918 .
• Repishti M, Hogan DL, Pratha V, Davydova L, Donowitz M, Tse CM, Isenberg JI . 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 . 2001 . 11408268 . 10.1152/ajpgi.2001.281.1.G159. 616434 .
• Malakooti J, Memark VC, Dudeja PK, Ramaswamy K . Molecular cloning and functional analysis of the human Na(+)/H(+) exchanger NHE3 promoter . Am. J. Physiol. Gastrointest. Liver Physiol. . 282 . 3 . G491-500 . 2002 . 11841999 . 10.1152/ajpgi.00273.2001 . 23652274 .
• Gekle M, Serrano OK, Drumm K, Mildenberger S, Freudinger R, Gassner B, Jansen HW, Christensen EI . NHE3 serves as a molecular tool for cAMP-mediated regulation of receptor-mediated endocytosis . Am. J. Physiol. Renal Physiol. . 283 . 3 . F549-58 . 2002 . 12167607 . 10.1152/ajprenal.00206.2001 .
• Kennedy DJ, Leibach FH, Ganapathy V, Thwaites DT . Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity . Pflügers Arch. . 445 . 1 . 139–46 . 2002 . 12397398 . 10.1007/s00424-002-0910-1 . 22183032 .
• Lee SH, Seok YS, Jung HH, Oh BH, Lee HM, Kwon SY, Jung KY . Expression of mRNA transcripts of the Na+/H+ and Cl-/HCO3- exchanger isoforms in human nasal mucosa . Acta Otolaryngol. . 122 . 8 . 866–71 . 2002 . 12542207 . 10.1080/003655402/000028045 .
• 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 . Biol. Pharm. Bull. . 26 . 2 . 148–55 . 2003 . 12576672 . 10.1248/bpb.26.148 . free .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nat. Biotechnol. . 21 . 5 . 566–9 . 2003 . 12665801 . 10.1038/nbt810 . 23783563 .

Notes and References

1. Web site: Entrez Gene: SLC9A3 Solute carrier family 9 (sodium/hydrogen exchanger), member 3.
2. Brant SR, Bernstein M, Wasmuth JJ, Taylor EW, McPherson JD, Li X, Walker S, Pouyssegur J, Donowitz M, Tse CM . Physical and genetic mapping of a human apical epithelial Na+/H+ exchanger (NHE3) isoform to chromosome 5p15.3 . Genomics . 15 . 3 . 668–72 . March 1993 . 8096830 . 10.1006/geno.1993.1122 . free .
3. http://www2.kumc.edu/ki/physiology/course/six/6_1.htm VI. Mechanisms of Salt & Water Reabsorption
4. 852 Book: Walter F., PhD. Boron . Medical Physiology: A Cellular And Molecular Approaoch . Elsevier/Saunders . 2005. 1-4160-2328-3 . Page 852
5. 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 . 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 . 2014 . 24622516 . 10.1126/scitranslmed.3007790 . 10741924 .
6. Klisic J, Hu MC, Nief V, Reyes L, Fuster D, Moe OW, Ambühl PM . Insulin activates Na(+)/H(+) exchanger 3: biphasic response and glucocorticoid dependence . Am J Physiol Renal Physiol . 3 . F532-9 . 2002 . 12167605 . 10.1152/ajprenal.00365.2001 . 283.
7. 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 . Biol. Pharm. Bull. . 26 . 2 . 148–55 . 2003 . 12576672 . 10.1248/bpb.26.148 . free .