The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [2,4,6-7,13]. In these epithelia, Na⁺ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC. The Na⁺ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na⁺/K⁺ ATPase located on the basolateral membrane [11]. As Na⁺ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na⁺ flow is accompanied by a flow of water accompanying Na⁺ ions [1]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [12]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [9,12].

In the respiratory tract and female reproductive tract, large segments of the epithelia are composed of multi-ciliated cells. In these cells, ENaC is located along the entire length of the cilia that cover the cell surface [5]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [5]. In contrast to ENaC, CFTR (ion transporter defective in cystic fibrosis) is located on non-cilial cell-surface [5]. In the vas deferens segment of the male reproductive tract, the luminal surface is covered by microvilli and stereocilia projections with backbones composed of actin filament bundles [13]. In these cells, both ENaC and the water channel aquaporin AQP9 are localized on these projections and also in the basal and smooth muscle layers [13]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation, and cell migration [5,7].

* Key recommended reading is highlighted with an asterisk

Berman JM, Brand C, Awayda MS. (2015) A long isoform of the epithelial sodium channel alpha subunit forms a highly active channel. Channels (Austin), 9 (1): 30-43. [PMID:25517724]

Boscardin E, Alijevic O, Hummler E, Frateschi S, Kellenberger S. (2016) The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br J Pharmacol, 173 (18): 2671-701. [PMID:27278329]

Bourque CW. (2008) Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci, 9 (7): 519-31. [PMID:18509340]

Eaton DC, Helms MN, Koval M, Bao HF, Jain L. (2009) The contribution of epithelial sodium channels to alveolar function in health and disease. Annu Rev Physiol, 71: 403-23. [PMID:18831683]

Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A. (2012) Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. Histochem Cell Biol, 137 (3): 339-53. [PMID:22207244]

* Hanukoglu I. (2017) ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters. FEBS J, 284 (4): 525-545. [PMID:27580245]

* Hanukoglu I, Hanukoglu A. (2016) Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene, 579 (2): 95-132. [PMID:26772908]

Kashlan OB, Kleyman TR. (2012) Epithelial Na(+) channel regulation by cytoplasmic and extracellular factors. Exp Cell Res, 318 (9): 1011-9. [PMID:22405998]

* Kellenberger S, Schild L. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol Rev, 67 (1): 1-35. [PMID:25287517]

Kleyman TR, Carattino MD, Hughey RP. (2009) ENaC at the cutting edge: regulation of epithelial sodium channels by proteases. J Biol Chem, 284 (31): 20447-51. [PMID:19401469]

* Kleyman TR, Eaton DC. (2020) Regulating ENaC's gate. Am J Physiol Cell Physiol, 318 (1): C150-C162. [PMID:31721612]

* Noreng S, Posert R, Bharadwaj A, Houser A, Baconguis I. (2020) Molecular principles of assembly, activation, and inhibition in epithelial sodium channel. Elife, 9. [PMID:32729833]

Palmer LG, Patel A, Frindt G. (2012) Regulation and dysregulation of epithelial Na+ channels. Clin Exp Nephrol, 16 (1): 35-43. [PMID:22038262]

Reddy MM, Stutts MJ. (2013) Status of fluid and electrolyte absorption in cystic fibrosis. Cold Spring Harb Perspect Med, 3 (1): a009555. [PMID:23284077]

* Rossier BC, Baker ME, Studer RA. (2015) Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev, 95 (1): 297-340. [PMID:25540145]

* Sharma S, Kumaran GK, Hanukoglu I. (2020) High-resolution imaging of the actin cytoskeleton and epithelial sodium channel, CFTR, and aquaporin-9 localization in the vas deferens. Mol Reprod Dev, 87 (2): 305-319. [PMID:31950584]

Shei RJ, Peabody JE, Kaza N, Rowe SM. (2018) The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis. Curr Opin Pharmacol, 43: 152-165. [PMID:30340955]

Soundararajan R, Pearce D, Hughey RP, Kleyman TR. (2010) Role of epithelial sodium channels and their regulators in hypertension. J Biol Chem, 285 (40): 30363-9. [PMID:20624922]

1. Bourque CW. (2008) Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci, 9 (7): 519-31. [PMID:18509340]

2. Canessa CM, Merillat AM, Rossier BC. (1994) Membrane topology of the epithelial sodium channel in intact cells. Am J Physiol, 267 (6 Pt 1): C1682-90. [PMID:7810611]

3. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC. (1994) Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature, 367 (6462): 463-7. [PMID:8107805]

4. Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC. (1994) Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry. J Cell Biol, 127 (6 Pt 2): 1907-21. [PMID:7806569]

5. Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A. (2012) Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. Histochem Cell Biol, 137 (3): 339-53. [PMID:22207244]

6. Hanukoglu I, Boggula VR, Vaknine H, Sharma S, Kleyman T, Hanukoglu A. (2017) Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages. Histochem Cell Biol, 147 (6): 733-748. [PMID:28130590]

7. Hanukoglu I, Hanukoglu A. (2016) Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene, 579 (2): 95-132. [PMID:26772908]

8. Kellenberger S, Gautschi I, Schild L. (2003) Mutations in the epithelial Na+ channel ENaC outer pore disrupt amiloride block by increasing its dissociation rate. Mol Pharmacol, 64 (4): 848-56. [PMID:14500741]

9. Knepper MA, Kwon TH, Nielsen S. (2015) Molecular physiology of water balance. N Engl J Med, 372 (14): 1349-58. [PMID:25830425]

10. Lu M, Echeverri F, Kalabat D, Laita B, Dahan DS, Smith RD, Xu H, Staszewski L, Yamamoto J, Ling J et al.. (2008) Small molecule activator of the human epithelial sodium channel. J Biol Chem, 283 (18): 11981-94. [PMID:18326490]

11. Pirahanchi Y, Jessu R, Aeddula NR. (2021) Physiology, Sodium Potassium Pump. StatPearls,. [PMID:30725773]

12. Rossier BC, Baker ME, Studer RA. (2015) Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev, 95 (1): 297-340. [PMID:25540145]

13. Sharma S, Kumaran GK, Hanukoglu I. (2020) High-resolution imaging of the actin cytoskeleton and epithelial sodium channel, CFTR, and aquaporin-9 localization in the vas deferens. Mol Reprod Dev, 87 (2): 305-319. [PMID:31950584]

Israel Hanukoglu Professor of Biochemistry and Molecular Biology Laboratory of Cell Biology Ariel University Ariel 40700 Israel