This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Snyder, P. M. Search for Related Content PubMed PubMed Citation Articles by Snyder, P. M.

Minireview: Regulation of Epithelial Na⁺ Channel Trafficking

Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Peter M. Snyder, 371 E.M.R.B., University of Iowa, Iowa City, Iowa 52242. E-mail: peter-snyder{at}uiowa.edu.

The epithelial Na⁺ channel (ENaC) is a pathway for Na⁺ transport across epithelia, including the kidney collecting duct, lung, and distal colon. ENaC is critical for Na⁺ homeostasis and blood pressure control; defects in ENaC function and regulation are responsible for inherited forms of hypertension and hypotension and may contribute to the pathogenesis of cystic fibrosis and other lung diseases. An emerging theme is that epithelial Na⁺ transport is regulated in large part through trafficking mechanisms that control ENaC expression at the cell surface. ENaC trafficking is regulated at multiple steps. Delivery of channels to the cell surface is regulated by aldosterone (and corticosteroids) and vasopressin, which increase ENaC synthesis and exocytosis, respectively. Conversely, endocytosis and degradation is controlled by a sequence located in the C terminus of , ß, and ENaC (PPPXYXXL). This sequence functions as an endocytosis motif and as a binding site for Nedd4-2, an E3 ubiquitin protein ligase that targets ENaC for degradation. Mutations that delete or disrupt this motif cause accumulation of channels at the cell surface, resulting in Liddle’s syndrome, an inherited form of hypertension. Nedd4-2 is a central convergence point for ENaC regulation by aldosterone and vasopressin; both induce phosphorylation of a common set of three Nedd4-2 residues, which blocks Nedd4-2 binding to ENaC. Thus, aldosterone and vasopressin regulate epithelial Na⁺ transport in part by altering ENaC trafficking to and from the cell surface.

This article has been cited by other articles:

				M. Althaus, M. Fronius, Y. Buchackert, I. Vadasz, W. G. Clauss, W. Seeger, R. Motterlini, and R. E. Morty Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels Am. J. Respir. Cell Mol. Biol., December 1, 2009; 41(6): 639 - 650. [Abstract] [Full Text] [PDF]

				A. Lazrak, K. E. Iles, G. Liu, D. L. Noah, J. W. Noah, and S. Matalon Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species FASEB J, November 1, 2009; 23(11): 3829 - 3842. [Abstract] [Full Text] [PDF]

				V. Bugaj, O. Pochynyuk, and J. D. Stockand Activation of the epithelial Na+ channel in the collecting duct by vasopressin contributes to water reabsorption Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1411 - F1418. [Abstract] [Full Text] [PDF]

				D. M. Collier and P. M. Snyder Extracellular Chloride Regulates the Epithelial Sodium Channel J. Biol. Chem., October 23, 2009; 284(43): 29320 - 29325. [Abstract] [Full Text] [PDF]

				A. Lazrak, I. Nita, D. Subramaniyam, S. Wei, W. Song, H.-L. Ji, S. Janciauskiene, and S. Matalon {alpha}1-Antitrypsin Inhibits Epithelial Na+ Transport In Vitro and In Vivo Am. J. Respir. Cell Mol. Biol., September 1, 2009; 41(3): 261 - 270. [Abstract] [Full Text] [PDF]

				T. R. Kleyman, M. D. Carattino, and R. P. Hughey ENaC at the Cutting Edge: Regulation of Epithelial Sodium Channels by Proteases J. Biol. Chem., July 31, 2009; 284(31): 20447 - 20451. [Abstract] [Full Text] [PDF]

				S. H. Kim, K. X. Kim, N. N. Raveendran, T. Wu, S. R. Pondugula, and D. C. Marcus Regulation of ENaC-mediated sodium transport by glucocorticoids in Reissner's membrane epithelium Am J Physiol Cell Physiol, March 1, 2009; 296(3): C544 - C557. [Abstract] [Full Text] [PDF]

				D. M. Collier and P. M. Snyder Extracellular Protons Regulate Human ENaC by Modulating Na+ Self-inhibition J. Biol. Chem., January 9, 2009; 284(2): 792 - 798. [Abstract] [Full Text] [PDF]

				R. S. Edinger, J. Lebowitz, H. Li, R. Alzamora, H. Wang, J. P. Johnson, and K. R. Hallows Functional Regulation of the Epithelial Na+ Channel by I{kappa}B Kinase-{beta} Occurs via Phosphorylation of the Ubiquitin Ligase Nedd4-2 J. Biol. Chem., January 2, 2009; 284(1): 150 - 157. [Abstract] [Full Text] [PDF]

				K. W. Rickert, P. Kelley, N. J. Byrne, R. E. Diehl, D. L. Hall, A. M. Montalvo, J. C. Reid, J. M. Shipman, B. W. Thomas, S. K. Munshi, et al. Structure of Human Prostasin, a Target for the Regulation of Hypertension J. Biol. Chem., December 12, 2008; 283(50): 34864 - 34872. [Abstract] [Full Text] [PDF]

				N. J. Foot, H. E. Dalton, L. M. Shearwin-Whyatt, L. Dorstyn, S.-S. Tan, B. Yang, and S. Kumar Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2 Blood, November 15, 2008; 112(10): 4268 - 4275. [Abstract] [Full Text] [PDF]

				K. K. Knight, D. M. Wentzlaff, and P. M. Snyder Intracellular Sodium Regulates Proteolytic Activation of the Epithelial Sodium Channel J. Biol. Chem., October 10, 2008; 283(41): 27477 - 27482. [Abstract] [Full Text] [PDF]

				S. Boulkroun, D. Ruffieux-Daidie, J.-J. Vitagliano, O. Poirot, R.-P. Charles, D. Lagnaz, D. Firsov, S. Kellenberger, and O. Staub Vasopressin-inducible ubiquitin-specific protease 10 increases ENaC cell surface expression by deubiquitylating and stabilizing sorting nexin 3 Am J Physiol Renal Physiol, October 1, 2008; 295(4): F889 - F900. [Abstract] [Full Text] [PDF]

				B. C. Rossier and L. Schild Epithelial Sodium Channel: Mendelian Versus Essential Hypertension Hypertension, October 1, 2008; 52(4): 595 - 600. [Full Text] [PDF]

				O. J. Mace, A. M. Woollhead, and D. L. Baines AICAR activates AMPK and alters PIP2 association with the epithelial sodium channel ENaC to inhibit Na+ transport in H441 lung epithelial cells J. Physiol., September 15, 2008; 586(18): 4541 - 4557. [Abstract] [Full Text] [PDF]

				S. K. Shenoy, K. Xiao, V. Venkataramanan, P. M. Snyder, N. J. Freedman, and A. M. Weissman Nedd4 Mediates Agonist-dependent Ubiquitination, Lysosomal Targeting, and Degradation of the {beta}2-Adrenergic Receptor J. Biol. Chem., August 8, 2008; 283(32): 22166 - 22176. [Abstract] [Full Text] [PDF]

				G. S. Stewart, J. H. O'Brien, and C. P. Smith Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters Am J Physiol Cell Physiol, July 1, 2008; 295(1): C121 - C129. [Abstract] [Full Text] [PDF]

				G. Fejes-Toth, G. Frindt, A. Naray-Fejes-Toth, and L. G. Palmer Epithelial Na+ channel activation and processing in mice lacking SGK1 Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1298 - F1305. [Abstract] [Full Text] [PDF]

				G. Zhou, L. A. Dada, and J. I. Sznajder Regulation of alveolar epithelial function by hypoxia Eur. Respir. J., May 1, 2008; 31(5): 1107 - 1113. [Abstract] [Full Text] [PDF]

				N. S. Raikwar and C. P. Thomas Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1157 - F1165. [Abstract] [Full Text] [PDF]

				R. Kabra, K. K. Knight, R. Zhou, and P. M. Snyder Nedd4-2 Induces Endocytosis and Degradation of Proteolytically Cleaved Epithelial Na+ Channels J. Biol. Chem., March 7, 2008; 283(10): 6033 - 6039. [Abstract] [Full Text] [PDF]

				B. Edemir, S. Reuter, R. Borgulya, R. Schroter, U. Neugebauer, G. Gabriels, and E. Schlatter Acute Rejection Modulates Gene Expression in the Collecting Duct J. Am. Soc. Nephrol., March 1, 2008; 19(3): 538 - 546. [Abstract] [Full Text] [PDF]

				N. Araki, M. Umemura, Y. Miyagi, M. Yabana, Y. Miki, K. Tamura, K. Uchino, R. Aoki, Y. Goshima, S. Umemura, et al. Expression, Transcription, and Possible Antagonistic Interaction of the Human Nedd4L Gene Variant: Implications for Essential Hypertension Hypertension, March 1, 2008; 51(3): 773 - 777. [Abstract] [Full Text] [PDF]

				C. Li, Y. Li, Y. Li, H. Liu, Z. Sun, J. Lu, and Y. Zhao Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter J. Mol. Endocrinol., January 1, 2008; 40(1): 3 - 12. [Abstract] [Full Text] [PDF]

				W. G. Hill, M. B. Butterworth, H. Wang, R. S. Edinger, J. Lebowitz, K. W. Peters, R. A. Frizzell, and J. P. Johnson The Epithelial Sodium Channel (ENaC) Traffics to Apical Membrane in Lipid Rafts in Mouse Cortical Collecting Duct Cells J. Biol. Chem., December 28, 2007; 282(52): 37402 - 37411. [Abstract] [Full Text] [PDF]

				K. M. Weixel, R. S. Edinger, L. Kester, C. J. Guerriero, H. Wang, L. Fang, T. R. Kleyman, P. A. Welling, O. A. Weisz, and J. P. Johnson Phosphatidylinositol 4-Phosphate 5-Kinase Reduces Cell Surface Expression of the Epithelial Sodium Channel (ENaC) in Cultured Collecting Duct Cells J. Biol. Chem., December 14, 2007; 282(50): 36534 - 36542. [Abstract] [Full Text] [PDF]

				R. Soundararajan, J. Wang, D. Melters, and D. Pearce Differential Activities of Glucocorticoid-induced Leucine Zipper Protein Isoforms J. Biol. Chem., December 14, 2007; 282(50): 36303 - 36313. [Abstract] [Full Text] [PDF]

				V. Pruliere-Escabasse, C. Planes, E. Escudier, P. Fanen, A. Coste, and C. Clerici Modulation of Epithelial Sodium Channel Trafficking and Function by Sodium 4-Phenylbutyrate in Human Nasal Epithelial Cells J. Biol. Chem., November 23, 2007; 282(47): 34048 - 34057. [Abstract] [Full Text] [PDF]

				O. Pochynyuk, J. D. Stockand, and A. Staruschenko Ion Channel Regulation by Ras, Rho, and Rab Small GTPases Experimental Biology and Medicine, November 1, 2007; 232(10): 1258 - 1265. [Abstract] [Full Text] [PDF]

				R. A. Fenton and M. A. Knepper Mouse Models and the Urinary Concentrating Mechanism in the New Millennium Physiol Rev, October 1, 2007; 87(4): 1083 - 1112. [Abstract] [Full Text] [PDF]

				Y. H. Kim, V. Pech, K. B. Spencer, W. H. Beierwaltes, L. A. Everett, E. D. Green, W. Shin, J. W. Verlander, R. L. Sutliff, and S. M. Wall Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1314 - F1324. [Abstract] [Full Text] [PDF]

				O. B. Kashlan, G. M. Mueller, M. Z. Qamar, P. A. Poland, A. Ahner, R. C. Rubenstein, R. P. Hughey, J. L. Brodsky, and T. R. Kleyman Small Heat Shock Protein {alpha}A-crystallin Regulates Epithelial Sodium Channel Expression J. Biol. Chem., September 21, 2007; 282(38): 28149 - 28156. [Abstract] [Full Text] [PDF]

				C. Shen, M.-J. Lin, A. Yaradanakul, V. Lariccia, J. A. Hill, and D. W. Hilgemann Dual control of cardiac Na+ Ca2+ exchange by PIP2: analysis of the surface membrane fraction by extracellular cysteine PEGylation J. Physiol., August 1, 2007; 582(3): 1011 - 1026. [Abstract] [Full Text] [PDF]

				R. Zhou, S. V. Patel, and P. M. Snyder Nedd4-2 Catalyzes Ubiquitination and Degradation of Cell Surface ENaC J. Biol. Chem., July 13, 2007; 282(28): 20207 - 20212. [Abstract] [Full Text] [PDF]

				J. A. Sullivan, M. J. Lewis, E. Nikko, and H. R.B. Pelham Multiple Interactions Drive Adaptor-Mediated Recruitment of the Ubiquitin Ligase Rsp5 to Membrane Proteins In Vivo and In Vitro Mol. Biol. Cell, July 1, 2007; 18(7): 2429 - 2440. [Abstract] [Full Text] [PDF]

				A. Staruschenko, O. Pochynyuk, A. Vandewalle, V. Bugaj, and J. D. Stockand Acute Regulation of the Epithelial Na+ Channel by Phosphatidylinositide 3-OH Kinase Signaling in Native Collecting Duct Principal Cells J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1652 - 1661. [Abstract] [Full Text] [PDF]

				O. Pochynyuk, A. Staruschenko, V. Bugaj, L. LaGrange, and J. D. Stockand Quantifying RhoA Facilitated Trafficking of the Epithelial Na+ Channel toward the Plasma Membrane with Total Internal Reflection Fluorescence-Fluorescence Recovery after Photobleaching J. Biol. Chem., May 11, 2007; 282(19): 14576 - 14585. [Abstract] [Full Text] [PDF]

				S. K. Shenoy Seven-Transmembrane Receptors and Ubiquitination Circ. Res., April 27, 2007; 100(8): 1142 - 1154. [Abstract] [Full Text] [PDF]

				H. Farhan, V. Reiterer, V. M. Korkhov, J. A. Schmid, M. Freissmuth, and H. H. Sitte Concentrative Export from the Endoplasmic Reticulum of the {gamma}-Aminobutyric Acid Transporter 1 Requires Binding to SEC24D J. Biol. Chem., March 9, 2007; 282(10): 7679 - 7689. [Abstract] [Full Text] [PDF]

				J. Nielsen, T.-H. Kwon, J. Frokiaer, M. A. Knepper, and S. Nielsen Maintained ENaC trafficking in aldosterone-infused rats during mineralocorticoid and glucocorticoid receptor blockade Am J Physiol Renal Physiol, January 1, 2007; 292(1): F382 - F394. [Abstract] [Full Text] [PDF]

				C. Mazzochi, D. J. Benos, and P. R. Smith Interaction of epithelial ion channels with the actin-based cytoskeleton Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1113 - F1122. [Abstract] [Full Text] [PDF]

				M. J. Page and E. Di Cera Role of na+ and k+ in enzyme function. Physiol Rev, October 1, 2006; 86(4): 1049 - 1092. [Abstract] [Full Text] [PDF]

				G. Chen, O. Frohlich, Y. Yang, J. D. Klein, and J. M. Sands Loss of N-Linked Glycosylation Reduces Urea Transporter UT-A1 Response to Vasopressin J. Biol. Chem., September 15, 2006; 281(37): 27436 - 27442. [Abstract] [Full Text] [PDF]

				O. Pochynyuk, J. Medina, N. Gamper, H. Genth, J. D. Stockand, and A. Staruschenko Rapid Translocation and Insertion of the Epithelial Na+ Channel in Response to RhoA Signaling J. Biol. Chem., September 8, 2006; 281(36): 26520 - 26527. [Abstract] [Full Text] [PDF]

				S. P. de Souza, R. Bezerra, L. Andrade, and A. C. Seguro Combined therapy with dialysis and glucocorticoids in critically ill renal failure patients Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1996 - 1998. [Full Text] [PDF]

				X. Liang, K. W. Peters, M. B. Butterworth, and R. A. Frizzell 14-3-3 Isoforms Are Induced by Aldosterone and Participate in Its Regulation of Epithelial Sodium Channels J. Biol. Chem., June 16, 2006; 281(24): 16323 - 16332. [Abstract] [Full Text] [PDF]

				O. Pochynyuk, Q. Tong, A. Staruschenko, H.-P. Ma, and J. D. Stockand Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides Am J Physiol Renal Physiol, May 1, 2006; 290(5): F949 - F957. [Abstract] [Full Text] [PDF]

				K. K. Knight, D. R. Olson, R. Zhou, and P. M. Snyder Liddle's syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage PNAS, February 21, 2006; 103(8): 2805 - 2808. [Abstract] [Full Text] [PDF]