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Function and Regulation of the Epithelial Na+ Channel ENaC

Daniela Rotin, Olivier Staub

10.1002/cphy.c200012

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

The Epithelial Na+ Channel, ENaC, comprised of 3 subunits (αβγ, or sometimes δβγENaC), plays a critical role in regulating salt and fluid homeostasis in the body. It regulates fluid reabsorption into the blood stream from the kidney to control blood volume and pressure, fluid absorption in the lung to control alveolar fluid clearance at birth and maintenance of normal airway surface liquid throughout life, and fluid absorption in the distal colon and other epithelial tissues. Moreover, recent studies have also revealed a role for sodium movement via ENaC in nonepithelial cells/tissues, such as endothelial cells in blood vessels and neurons. Over the past 25 years, major advances have been made in our understanding of ENaC structure, function, regulation, and role in human disease. These include the recently solved three‐dimensional structure of ENaC, ENaC function in various tissues, and mutations in ENaC that cause a hereditary form of hypertension (Liddle syndrome), salt‐wasting hypotension (PHA1), or polymorphism in ENaC that contributes to other diseases (such as cystic fibrosis). Moreover, great strides have been made in deciphering the regulation of ENaC by hormones (e.g., the mineralocorticoid aldosterone, glucocorticoids, vasopressin), ions (e.g., Na+), proteins (e.g., the ubiquitin‐protein ligase NEDD4‐2, the kinases SGK1, AKT, AMPK, WNKs & mTORC2, and proteases), and posttranslational modifications [e.g., (de)ubiquitylation, glycosylation, phosphorylation, acetylation, palmitoylation]. Characterization of ENaC structure, function, regulation, and role in human disease, including using animal models, are described in this article, with a special emphasis on recent advances in the field. © 2021 American Physiological Society. Compr Physiol 11:2017‐2045, 2021.

Figure 1. Figure 1. ENaC structure and stoichiometry. Cryo‐EM map of inactive αβγENaC, with each subunit lacking its intracellular C‐terminal region, and bearing inactivating mutations in its ectodomain (ΔENaC). Two Fab fragments (Fv 7B1&10D4) are attached to the α and β subunits to stabilize the complex, which is collectively called the ΔENaC‐7B1/10D4 complex. (A) The complex is viewed parallel (Left), and perpendicular (Right), to the plasma membrane. The α, β, and γ subunits are colored blue, red, and magenta, respectively. The 7B1 and 10D4 Fv densities are colored green and wheat, respectively. (B) Cartoon (ribbon diagram) representation of the ΔENaC‐7B1/10D4 complex viewed and colored as in (A). (C) Schematic secondary structure elements of the ENaC extracellular domain. Knuckle: cyan; Palm: yellow; Finger: purple; GRIP: blue; β‐ball: orange; Thumb: green. The dimensions of the complex and ΔENaC alone are indicated. Reproduced, with permission, from Noreng S, et al., 2018 251. Licenced under CC BY 4.0.
Figure 2. Figure 2. ENaC activation by proteases. (A) Un‐cleaved ENaC exhibits low channel activity (Left). The ectodomain of α and γ ENaC contain proteases cleavage sites (arrowheads), and upon their cleavage by Furin at the Golgi (black arrowheads), which releases an inhibitory track in αENaC, the channel becomes partially active (Middle). Once at the plasma membrane, a second extracellular protease (such as prostasin, Kallikrein, Matriptase, and others—green arrowhead) cleaves γENaC and releases a second inhibitory fragment, leading to full channel activation (Right). Modified, with permission, from Kleyman TR and Eaton DC, 2020 179. (B) Schematic representation of the mechanism of protease‐dependent gating in a single ENaC subunit. Removal of the protease‐sensitive segments of the GRIP domain (Left) induces conformational changes in the finger and thumb domains (Right), which is predicted to couple to ion channel gating through the wrist. Reproduced, with permission, from Noreng S, et al., 2018 251. Licenced under CC BY 4.0.
Figure 3. Figure 3. Regulation of ENaC by NEDD4‐2 and by ubiquitylation. (A) The ubiquitin ligase NEDD4‐2 (Nedd4‐2) binds, via its WW domains, to the PY motifs of the ENaC subunits, leading to ENaC ubiquitylation and endocytosis, hence reduced Na+ entry into cells. (B) Several kinases (activated by specific hormones or inflammation) phosphorylate Nedd4‐2, leading to binding of 14‐3‐3 proteins to the phosphorylated sites and thus impaired ability of Nedd4‐2 to bind ENaC and ubiquitylate it, causing ENaC retention at the plasma membrane and elevated Na+ influx. (C) Metabolic stress that activates AMPK leads to binding of β1‐Pix to 14‐3‐3, preventing 14‐3‐3 from blocking the access of Nedd4‐2 to ENaC, thus resulting in enhanced ENaC ubiquitylation and endocytosis. (D) Specific DUBs oppose the effect of Nedd4‐2 on ENaC by either deubiquitylating the channel at the plasma membrane (Usp‐45) or by deubiquitylating the channel in early/sorting endosomes after endocytosis (Uch‐L3, Usp8), leading to channel recycling back to the plasma membrane instead of its degradation by the lysosomes. (E) In Liddle syndrome, where the PY motif of β (or γ) ENaC is mutated or deleted, the ability of Nedd4‐2 to bind ENaC is impaired, resulting in channel retention at the cell surface and increased Na+ entry into cells.


Figure 1. ENaC structure and stoichiometry. Cryo‐EM map of inactive αβγENaC, with each subunit lacking its intracellular C‐terminal region, and bearing inactivating mutations in its ectodomain (ΔENaC). Two Fab fragments (Fv 7B1&10D4) are attached to the α and β subunits to stabilize the complex, which is collectively called the ΔENaC‐7B1/10D4 complex. (A) The complex is viewed parallel (Left), and perpendicular (Right), to the plasma membrane. The α, β, and γ subunits are colored blue, red, and magenta, respectively. The 7B1 and 10D4 Fv densities are colored green and wheat, respectively. (B) Cartoon (ribbon diagram) representation of the ΔENaC‐7B1/10D4 complex viewed and colored as in (A). (C) Schematic secondary structure elements of the ENaC extracellular domain. Knuckle: cyan; Palm: yellow; Finger: purple; GRIP: blue; β‐ball: orange; Thumb: green. The dimensions of the complex and ΔENaC alone are indicated. Reproduced, with permission, from Noreng S, et al., 2018 251. Licenced under CC BY 4.0.


Figure 2. ENaC activation by proteases. (A) Un‐cleaved ENaC exhibits low channel activity (Left). The ectodomain of α and γ ENaC contain proteases cleavage sites (arrowheads), and upon their cleavage by Furin at the Golgi (black arrowheads), which releases an inhibitory track in αENaC, the channel becomes partially active (Middle). Once at the plasma membrane, a second extracellular protease (such as prostasin, Kallikrein, Matriptase, and others—green arrowhead) cleaves γENaC and releases a second inhibitory fragment, leading to full channel activation (Right). Modified, with permission, from Kleyman TR and Eaton DC, 2020 179. (B) Schematic representation of the mechanism of protease‐dependent gating in a single ENaC subunit. Removal of the protease‐sensitive segments of the GRIP domain (Left) induces conformational changes in the finger and thumb domains (Right), which is predicted to couple to ion channel gating through the wrist. Reproduced, with permission, from Noreng S, et al., 2018 251. Licenced under CC BY 4.0.


Figure 3. Regulation of ENaC by NEDD4‐2 and by ubiquitylation. (A) The ubiquitin ligase NEDD4‐2 (Nedd4‐2) binds, via its WW domains, to the PY motifs of the ENaC subunits, leading to ENaC ubiquitylation and endocytosis, hence reduced Na+ entry into cells. (B) Several kinases (activated by specific hormones or inflammation) phosphorylate Nedd4‐2, leading to binding of 14‐3‐3 proteins to the phosphorylated sites and thus impaired ability of Nedd4‐2 to bind ENaC and ubiquitylate it, causing ENaC retention at the plasma membrane and elevated Na+ influx. (C) Metabolic stress that activates AMPK leads to binding of β1‐Pix to 14‐3‐3, preventing 14‐3‐3 from blocking the access of Nedd4‐2 to ENaC, thus resulting in enhanced ENaC ubiquitylation and endocytosis. (D) Specific DUBs oppose the effect of Nedd4‐2 on ENaC by either deubiquitylating the channel at the plasma membrane (Usp‐45) or by deubiquitylating the channel in early/sorting endosomes after endocytosis (Uch‐L3, Usp8), leading to channel recycling back to the plasma membrane instead of its degradation by the lysosomes. (E) In Liddle syndrome, where the PY motif of β (or γ) ENaC is mutated or deleted, the ability of Nedd4‐2 to bind ENaC is impaired, resulting in channel retention at the cell surface and increased Na+ entry into cells.
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Article Title: Function and Regulation of the Epithelial Na+ Channel ENaC
 

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Daniela Rotin, Olivier Staub. Function and Regulation of the Epithelial Na+ Channel ENaC. Compr Physiol 2021, 11: 2017-2045. doi: 10.1002/cphy.c200012