Table 1.
The cation proton antiporter 1 (CPA1) superfamily.
| Subdivision | Coding Gene | Molecular Weight | Inhibitors | Localization | Function | Ref. |
|---|---|---|---|---|---|---|
| NHE1 | SLC9A1 | 820aa, ~90 kDa | Amiloride, EIPA, HMA, DMA, HOE-694, SM-20550, S-3226, Clonidine, Cimetidine | It is ubiquitously expressed in nearly all mammalian tissue types and localized basolaterally in every epithelial cell, except in the choroid plexus and syncytio-throphoblast of the human placenta where it expresses apically | It regulates cell volume, intracellular pH, proliferation, differentiation, and apoptosis | [8,13,14,15,16] |
| NHE2 | SLC9A2 | 812aa, ~90 kDa | Amiloride, EIPA, DMA, S-3226 | Highly expressed in intestine and kidney | The physiologic role of NHE2 still remains elusive despite its wide expression pattern with higher expression levels in the intestine and the kidney | [16,17,18,19] |
| NHE3 | SLC9A3 | 834aa, ~92 kDa | Amiloride, Tenapanor, HMA, DMA, HOE-694, Zoniporide, S-3226, Clonidine, Cimetidine | Highly expressed in intestine and kidney | It plays an important role in mediating intestinal electroneutral NaCl absorption in mammals. It also contributes to the absorption of other nutrients, such as amino acids and dipeptides through H+ gradients | [8,16,19,20,21,22] |
| NHE4 | SLC9A4 | 798aa, ~70 kDa | Amiloride, EIPA | NHE4 is highly expressed in the stomach while its expression is low in kidney, intestine, brain, ureter, skeletal muscle, heart, liver, and spleen | It plays a major role in intracellular pH homeostasis | [16,19,23,24] |
| NHE5 | SLC9A5 | 896aa, ~100 kDa | Amiloride, EIPA, HMA, HOE-694, Cimetidine | Predominantly expressed in brain | It regulates growth factor signaling, integrin trafficking, and degradation of glioma cells. It also functions as a negative regulator of dendritic spine growth | [16,19,25,26] |
| NHE6 | SLC9A6 | 669aa, ~85 kDa | Rimeporide | It is highly expressed in skeletal muscles, brain, and heart | It functions to regulate intramitochondrial Na+ and H+ gradients | [19,27,28,29,30] |
| NHE7 | SLC9A7 | 725aa, ~80 kDa | Amiloride | Predominantly localized in the trans-Golgi network | It is prominently expressed in the trans-Golgi network and in the mid-trans-Golgi stacks, and functions as a K+/H+ exchanger in controlling organelle volume through transmembrane K+ flux | [16,19,31,32] |
| NHE8 | SLC9A8 | 581aa, ~65 kDa | HOE-642, S-3226 | NHE8 protein has been detected in the plasma membrane, Golgi apparatus, and endosomes. It is ubiquitously expressed in many tissues | NHE8 is involved in electroneutral NaCl transport, cell volume regulation, cellular adhesion, migration, and proliferation | [6,7,9,19,33,34] |
| NHE9 | SLC9A9 | 645aa, ~72 kDa | Unknown | It is expressed mostly in heart, skeletal muscle, and brain | It transports the protons out of the endosomal lumen in exchange for Na+/K+, thus controlling the pH of endosomal lumens | [35,36] |
| NHE10 | SLC9C1 | 1177aa, ~135 kDa | Unknown | Predominantly expressed in testis and in osteoclasts | NHE10 is associated with sperm motility and fertility, and it is required for osteoclasts differentiation and survivor | [19,37,38,39,40,41] |
| NHE11 | SLC9C2 | 1124aa, ~130 kDa | Unknown | Expressed in the brain, choroid plexus, testis, and uterine tube | Unknown | [19] |
| NHA1 | SLC9B1 | 515aa, ~55 kDa | Unknown | Expressed in testis | It regulates the pH and the cell volume | [19,42] |
| NHA2 | SLC9B2 | 537aa, ~57 kDa | Phloretin | It is ubiquitously expressed in mouse tissues | It regulates the pH and the cell volume | [19,43,44] |
EIPA = 5-N-ethyl-N-isopropyl-amiloride; HMA = 5-N,N-hexamethylene-amiloride; DMA = 5-N,N-dimethyl-amiloride; HOE-694 = 3-methylsulphonyl-4-piperidinobenzoyl, guanidine hydrochloride; SM-20550 = N-aminoiminomethyl-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid; S-3226 = 3-2-3-guanidino-2-methyl-3-oxopropenyl-5-methyl-phenyl-N-isopropylidene-2-methyl-acrylamide dihydrochloride.