Epithelial sodium channels (ENaC)
The epithelial sodium channels (ENaC) mediates sodium reabsorption in the aldosterone-sensitive distal part of the nephron and the collecting duct of the kidney. ENaC is found on other tight epithelial tissues such as the airways, distal colon and exocrine glands. ENaC activity is tightly regulated in the kidney by aldosterone, angiotensin II, vasopressin, insulin and glucocorticoids; this fine regulation of ENaC is essential to maintain sodium balance between daily intake and urinary excretion of sodium, circulating volume and blood pressure. ENaC expression is also vital for clearance of foetal lung fluid, and to maintain air-surface-liquid [11,15]. Sodium reabsorption is suppressed by the ‘potassium-sparing’ diuretics amiloride and triamterene. ENaC is a heteromultimeric channel made of homologous α β and γ subunits. The primary structure of αENaC subunit was identified by expression cloning [4]; β and γ ENaC were identified by functional complementation of the α subunit [5]. Each ENaC subunit contains 2 TM α helices connected by a large extracellular loop and short cytoplasmic amino- and carboxy-termini. The stoichiometry of the epithelial sodium channel in the kidney and related epithelia is, by homology with the structurally related channel ASIC1a, thought to be a heterotrimer of 1α:1β:1γ subunits [9].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Bhalla, V; Hallows, KR. (2008) Mechanisms of ENaC regulation and clinical implications. J. Am. Soc. Nephrol., 19 (10): 1845-54. [PMID:18753254]
Bonny, O; Hummler, E. (2000) Dysfunction of epithelial sodium transport: from human to mouse. Kidney Int., 57 (4): 1313-8. [PMID:10760060]
Bubien, JK. (2010) Epithelial Na+ channel (ENaC), hormones, and hypertension. J. Biol. Chem., 285 (31): 23527-31. [PMID:20460373]
Butterworth, MB. (2010) Regulation of the epithelial sodium channel (ENaC) by membrane trafficking. Biochim. Biophys. Acta, 1802 (12): 1166-77. [PMID:20347969]
Hamm, LL; Feng, Z; Hering-Smith, KS. (2010) Regulation of sodium transport by ENaC in the kidney. Curr. Opin. Nephrol. Hypertens., 19 (1): 98-105. [PMID:19996890]
Hummler, E; Vallon, V. (2005) Lessons from mouse mutants of epithelial sodium channel and its regulatory proteins. J. Am. Soc. Nephrol., 16 (11): 3160-6. [PMID:16192419]
Kellenberger, S; Schild, L. (2002) Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol. Rev., 82 (3): 735-67. [PMID:12087134]
Kitamura, K; Tomita, K. (2010) Regulation of renal sodium handling through the interaction between serine proteases and serine protease inhibitors. Clin. Exp. Nephrol., 14 (5): 405-10. [PMID:20535627]
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]
Loffing, J; Korbmacher, C. (2009) Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch., 458 (1): 111-35. [PMID:19277701]
Ma, HP; Chou, CF; Wei, SP; Eaton, DC. (2007) Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflugers Arch., 455 (1): 169-80. [PMID:17605040]
Planès, C; Caughey, GH. (2007) Regulation of the epithelial Na+ channel by peptidases. Curr. Top. Dev. Biol., 78: 23-46. [PMID:17338914]
Pochynyuk, O; Bugaj, V; Stockand, JD. (2008) Physiologic regulation of the epithelial sodium channel by phosphatidylinositides. Curr. Opin. Nephrol. Hypertens., 17 (5): 533-40. [PMID:18695396]
Rossier, BC; Pradervand, S; Schild, L; Hummler, E. (2002) Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu. Rev. Physiol., 64: 877-97. [PMID:11826291]
Rossier, BC; Stutts, MJ. (2009) Activation of the epithelial sodium channel (ENaC) by serine proteases. Annu. Rev. Physiol., 71: 361-79. [PMID:18928407]
Rotin, D; Schild, L. (2008) ENaC and its regulatory proteins as drug targets for blood pressure control. Curr Drug Targets, 9 (8): 709-16. [PMID:18691017]
Schild, L. (2004) The epithelial sodium channel: from molecule to disease. Rev. Physiol. Biochem. Pharmacol., 151: 93-107. [PMID:15146350]
Schild, L. (2010) The epithelial sodium channel and the control of sodium balance. Biochim. Biophys. Acta, 1802 (12): 1159-65. [PMID:20600867]
1. Barker, PM; Strang, LB; Walters, DV. (1990) The role of thyroid hormones in maturation of the adrenaline-sensitive lung liquid reabsorptive mechanism in fetal sheep. J. Physiol. (Lond.), 424: 473-85. [PMID:2391659]
2. Boase, NA; Rychkov, GY; Townley, SL; Dinudom, A; Candi, E; Voss, AK; Tsoutsman, T; Semsarian, C; Melino, G; Koentgen, F; et al.. (2011) Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nat Commun, 2: 287. [PMID:21505443]
3. Bonny, O; Hummler, E. (2000) Dysfunction of epithelial sodium transport: from human to mouse. Kidney Int., 57 (4): 1313-8. [PMID:10760060]
4. Canessa, CM; Horisberger, JD; Rossier, BC. (1993) Epithelial sodium channel related to proteins involved in neurodegeneration. Nature, 361 (6411): 467-70. [PMID:8381523]
5. 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]
6. Debonneville, C; Flores, SY; Kamynina, E; Plant, PJ; Tauxe, C; Thomas, MA; Münster, C; Chraïbi, A; Pratt, JH; Horisberger, JD; et al.. (2001) Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J., 20 (24): 7052-9. [PMID:11742982]
7. Friedrich, B; Feng, Y; Cohen, P; Risler, T; Vandewalle, A; Bröer, S; Wang, J; Pearce, D; Lang, F. (2003) The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC. Pflugers Arch., 445 (6): 693-6. [PMID:12632189]
8. Garcia-Caballero, A; Rasmussen, JE; Gaillard, E; Watson, MJ; Olsen, JC; Donaldson, SH; Stutts, MJ; Tarran, R. (2009) SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc. Natl. Acad. Sci. U.S.A., 106 (27): 11412-7. [PMID:19541605]
9. Gonzales, EB; Kawate, T; Gouaux, E. (2009) Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature, 460 (7255): 599-604. [PMID:19641589]
10. Guan, Y; Hao, C; Cha, DR; Rao, R; Lu, W; Kohan, DE; Magnuson, MA; Redha, R; Zhang, Y; Breyer, MD. (2005) Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat. Med., 11 (8): 861-6. [PMID:16007095]
11. Hummler, E; Barker, P; Gatzy, J; Beermann, F; Verdumo, C; Schmidt, A; Boucher, R; Rossier, BC. (1996) Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat. Genet., 12 (3): 325-8. [PMID:8589728]
12. 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]
13. Kitamura, K; Tomita, K. (2010) Regulation of renal sodium handling through the interaction between serine proteases and serine protease inhibitors. Clin. Exp. Nephrol., 14 (5): 405-10. [PMID:20535627]
14. 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]
15. Loffing, J; Korbmacher, C. (2009) Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch., 458 (1): 111-35. [PMID:19277701]
16. 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]
17. Ma, HP; Chou, CF; Wei, SP; Eaton, DC. (2007) Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflugers Arch., 455 (1): 169-80. [PMID:17605040]
18. Maekawa, A; Kakizoe, Y; Miyoshi, T; Wakida, N; Ko, T; Shiraishi, N; Adachi, M; Tomita, K; Kitamura, K. (2009) Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension. J. Hypertens., 27 (1): 181-9. [PMID:19145783]
19. Morris, RG; Schafer, JA. (2002) cAMP increases density of ENaC subunits in the apical membrane of MDCK cells in direct proportion to amiloride-sensitive Na(+) transport. J. Gen. Physiol., 120 (1): 71-85. [PMID:12084777]
20. Planès, C; Caughey, GH. (2007) Regulation of the epithelial Na+ channel by peptidases. Curr. Top. Dev. Biol., 78: 23-46. [PMID:17338914]
21. Pochynyuk, O., Bugaj, V., Rieg, T., Insel, P. A., Mironova, E., Vallon, V. and Stockand, J. D. (2008) Paracrine regulation of the epithelial Na+ channel in the mammalian collecting duct by purinergic P2Y2 receptor tone. J Biol Chem, 283: 36599-36607. [PMID:18981175]
22. Richard, K; Ramminger, SJ; Forsyth, L; Burchell, A; Wilson, SM. (2004) Thyroid hormone potentiates glucocorticoid-evoked airway Na+ transport without affecting alpha-ENaC transcription. FEBS Lett., 576 (3): 339-42. [PMID:15498559]
23. Rossier, BC; Stutts, MJ. (2009) Activation of the epithelial sodium channel (ENaC) by serine proteases. Annu. Rev. Physiol., 71: 361-79. [PMID:18928407]
24. Rotin, D; Schild, L. (2008) ENaC and its regulatory proteins as drug targets for blood pressure control. Curr Drug Targets, 9 (8): 709-16. [PMID:18691017]
25. Sayegh, R; Auerbach, SD; Li, X; Loftus, RW; Husted, RF; Stokes, JB; Thomas, CP. (1999) Glucocorticoid induction of epithelial sodium channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 5'-flanking region of the human epithelial sodium channel alpha subunit gene. J. Biol. Chem., 274 (18): 12431-7. [PMID:10212217]
26. Schild, L. (2010) The epithelial sodium channel and the control of sodium balance. Biochim. Biophys. Acta, 1802 (12): 1159-65. [PMID:20600867]
27. Staub, O; Dho, S; Henry, P; Correa, J; Ishikawa, T; McGlade, J; Rotin, D. (1996) WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. EMBO J., 15 (10): 2371-80. [PMID:8665844]
28. Yang, LM; Rinke, R; Korbmacher, C. (2006) Stimulation of the epithelial sodium channel (ENaC) by cAMP involves putative ERK phosphorylation sites in the C termini of the channel's beta- and gamma-subunit. J. Biol. Chem., 281 (15): 9859-68. [PMID:16476738]
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Data in the table refer to the αβγ heteromer. There are several human diseases resulting from mutations in ENaC subunits. Liddle’s syndrome (including features of salt-sensitive hypertension and hypokalemia), is associated with gain of function mutations in the β and γ subunits leading to defective ENaC ubiquitylation and increased stability of active ENaC at the cell surface [24,26-27]. Enzymes that deubiquitylate ENaC increase its function in vivo. Pseudohypoaldosteronism type 1 (PHA-1) can occur through either mutations in the gene encoding the mineralocorticoid receptor, or loss of function mutations in genes encoding ENaC subunits [3]. Regulation of ENaC by phosphoinositides may underlie insulin-evoked renal Na+ retention that can complicate the clinical management of type 2 diabetes using insulin-sensitizing thiazolidinedione drugs [10].