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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Sodium/hydrogen exchangers or sodium/proton antiports are a family of transporters that maintain cellular pH by utilising the sodium gradient across the plasma membrane to extrude protons produced by metabolism, in a stoichiometry of 1 Na+ (in) : 1 H+ (out). Several isoforms, NHE6, NHE7, NHE8 and NHE9 appear to locate on intracellular membranes [5-7]. Li+ and NH4+, but not K+, ions may also be transported by some isoforms. Modelling of the topology of these transporters indicates 12 TM regions with an extended intracellular C-terminus containing multiple regulatory sites.
NHE1 is considered to be a ubiquitously-expressed ‘housekeeping’ transporter. NHE3 is highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm  and osteoclasts ; gene disruption results in infertile male mice .
* Key recommended reading is highlighted with an asterisk
* Bobulescu IA, Moe OW. (2009) Luminal Na(+)/H (+) exchange in the proximal tubule. Pflugers Arch., 458 (1): 5-21. [PMID:18853182]
* Casey JR, Grinstein S, Orlowski J. (2010) Sensors and regulators of intracellular pH. Nat. Rev. Mol. Cell Biol., 11 (1): 50-61. [PMID:19997129]
* Christensen HL, Nguyen AT, Pedersen FD, Damkier HH. (2013) Na(+) dependent acid-base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol, 4: 304. [PMID:24155723]
* Donowitz M, Ming Tse C, Fuster D. (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na⁺/H⁺ exchangers. Mol. Aspects Med., 34 (2-3): 236-51. [PMID:23506868]
* Kato A, Romero MF. (2011) Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol., 73: 261-81. [PMID:21054167]
* Kemp G, Young H, Fliegel L. (2008) Structure and function of the human Na+/H+ exchanger isoform 1. Channels (Austin), 2 (5): 329-36. [PMID:19001864]
* Ohgaki R, van IJzendoorn SC, Matsushita M, Hoekstra D, Kanazawa H. (2011) Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry, 50 (4): 443-50. [PMID:21171650]
Orlowski J, Grinstein S. (2004) Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch., 447 (5): 549-65. [PMID:12845533]
* Parker MD, Myers EJ, Schelling JR. (2015) Na+-H+ exchanger-1 (NHE1) regulation in kidney proximal tubule. Cell. Mol. Life Sci., 72 (11): 2061-74. [PMID:25680790]
* Ruffin VA, Salameh AI, Boron WF, Parker MD. (2014) Intracellular pH regulation by acid-base transporters in mammalian neurons. Front Physiol, 5: 43. [PMID:24592239]
Slepkov ER, Rainey JK, Sykes BD, Fliegel L. (2007) Structural and functional analysis of the Na+/H+ exchanger. Biochem. J., 401 (3): 623-33. [PMID:17209804]
1. Charmot D, Jacobs JW, Leadbetter MR, Navre M, Carreras C, Bell N. (2013) Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders. Patent number: US8541448 B2. Assignee: Ardelyx, Inc.. Priority date: 31/12/2008. Publication date: 24/09/2013.
2. Counillon L, Scholz W, Lang HJ, Pouysségur J. (1993) Pharmacological characterization of stably transfected Na+/H+ antiporter isoforms using amiloride analogs and a new inhibitor exhibiting anti-ischemic properties. Mol. Pharmacol., 44 (5): 1041-5. [PMID:8246907]
3. Lee SH, Kim T, Park ES, Yang S, Jeong D, Choi Y, Rho J. (2008) NHE10, an osteoclast-specific member of the Na+/H+ exchanger family, regulates osteoclast differentiation and survival [corrected]. Biochem. Biophys. Res. Commun., 369 (2): 320-6. [PMID:18269914]
4. Masereel B, Pochet L, Laeckmann D. (2003) An overview of inhibitors of Na(+)/H(+) exchanger. Eur J Med Chem, 38 (6): 547-54. [PMID:12832126]
5. Miyazaki E, Sakaguchi M, Wakabayashi S, Shigekawa M, Mihara K. (2001) NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell. J. Biol. Chem., 276 (52): 49221-7. [PMID:11641397]
6. Nakamura N, Tanaka S, Teko Y, Mitsui K, Kanazawa H. (2005) Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J. Biol. Chem., 280 (2): 1561-72. [PMID:15522866]
7. Numata M, Orlowski J. (2001) Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J. Biol. Chem., 276 (20): 17387-94. [PMID:11279194]
8. Tse CM, Levine SA, Yun CH, Brant SR, Pouyssegur J, Montrose MH, Donowitz M. (1993) Functional characteristics of a cloned epithelial Na+/H+ exchanger (NHE3): resistance to amiloride and inhibition by protein kinase C. Proc. Natl. Acad. Sci. U.S.A., 90 (19): 9110-4. [PMID:8415663]
9. Tse CM, Levine SA, Yun CH, Montrose MH, Little PJ, Pouyssegur J, Donowitz M. (1993) Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H+ exchanger isoform (NHE-2). J. Biol. Chem., 268 (16): 11917-24. [PMID:7685025]
10. Wang D, King SM, Quill TA, Doolittle LK, Garbers DL. (2003) A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility. Nat. Cell Biol., 5 (12): 1117-22. [PMID:14634667]
Database page citation:
SLC9 family of sodium/hydrogen exchangers. Accessed on 14/02/2016. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=181.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Transporters. Br J Pharmacol. 172: 6110-6202.