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 [10] and osteoclasts [3]; gene disruption results in infertile male mice [10].

Analogues of the non-selective cation transport inhibitor amiloride appear to inhibit NHE function through competitive inhibition of the extracellular Na⁺ binding site. The more selective amiloride analogues MPA and ethylisopropylamiloride exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [2,8-9].

* Key recommended reading is highlighted with an asterisk

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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]

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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]

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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 USA, 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]