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 [3-5]. 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. NHE2 and NHE3 are highly expressed in the intestine and kidneys and regulate sodium movements in those tissues. NHE10 is present in sperm [8] and osteoclasts [2]; gene disruption results in infertile male mice [8].

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 EIPA exhibit a rank order of affinity of inhibition of NHE1 > NHE2 > NHE3 [1,6-7].

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1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]