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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.

	Abstract

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
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.

	Introduction

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
THE EPITHELIAL NA⁺ channel (ENaC) forms a pathway for the transport of Na⁺ across a variety of epithelia. The rate of Na⁺ transport must vary dramatically to maintain Na⁺ and volume homeostasis in the face of extremes of Na⁺ intake. Thus, ENaC function is tightly regulated. In contrast to voltage- and ligand-gated ion channels, which are regulated through rapid changes in channel opening and closing (gating), ENaC is regulated in large part through mechanisms that control its expression at the cell surface, akin to the regulation of many receptors and transporters. Although such a mechanism sacrifices speed, its advantage is a potentially larger dynamic range. Previous work suggests that ENaC trafficking is highly regulated, both at the level of ENaC movement to the cell surface, as well as ENaC endocytosis and degradation. Moreover, defects in ENaC trafficking are responsible for inherited forms of hypertension and hypotension (1). Thus, elucidating the mechanisms that regulate ENaC trafficking is critical to our understanding of Na⁺ transport and Na⁺ homeostasis. Here, we will review recent work on the regulation of ENaC trafficking and the mechanisms by which ENaC mutations disrupt trafficking and cause disease.

	ENaC in Epithelial Na+ Transport

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
ENaC channels are composed of three homologous subunits (-, ß-, and ENaC; Fig. 1) (2, 3, 4, 5, 6, 7). Each subunit has two transmembrane segments, a large extracellular domain (comprising > 80% of the protein) and cytoplasmic N and C termini (8, 9, 10). The three subunits heteromultimerize to form a functional complex, although the total number of subunits (reports vary from four to nine subunits) and stoichiometry remain uncertain (11, 12, 13, 14, 15, 16). ENaC is highly selective for Na⁺ over K⁺, and the channel pore is blocked by the diuretic amiloride (17, 18).

View larger version (10K): [in this window] [in a new window]   FIG. 1. ENaC structural domains. Schematic lineup of -, ß-, and ENaC. Membrane-spanning domains (M1 and M2), ubiquitination sites (Ub), furin cleavage sites, and PPPXYXXL motifs are indicated.

The regulated transport of Na⁺ across epithelia via ENaC is critical for a variety of processes. For example, in the kidney collecting duct, Na⁺ transport is necessary to maintain Na⁺ and volume homeostasis and to control blood pressure (19). Under conditions of Na⁺ deprivation, Na⁺ transport is increased to prevent volume depletion. In contrast, Na⁺ transport is decreased under conditions of Na⁺ excess. Defects in the regulation of Na⁺ transport underlie all of the known inherited forms of hypertension (1). In the lung, Na⁺ transport is critical to control the volume and composition of fluid lining the airway. At the time of birth, Na⁺ (and hence, fluid) is transported from the airway lumen to the blood, converting the lung from a fluid-filled to a gas-filled organ to facilitate gas exchange (20, 21). Later in life, Na⁺ transport prevents excessive fluid accumulation (pulmonary edema) and plays an important role in host defense by maintaining optimal conditions for mucociliary clearance (22) and the function of endogenous antibacterial molecules (23, 24). Defects in the regulation of Na⁺ transport in the lung may contribute to the pathogenesis of lung diseases including cystic fibrosis.

	Hormonal Regulation of ENaC

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Na⁺ transport via ENaC is regulated principally by two hormonal pathways. In states of volume depletion, decreased renal perfusion results in release of renin from the juxtaglomerular apparatus, activating the renin-angiotensin-aldosterone pathway. Binding of aldosterone to the mineralocorticoid receptor activates transcription of a variety of genes, which increases ENaC current after a lag time of 1–3 h (25, 26). Corticosteroids (via glucocorticoid receptors) increase Na⁺ transport through similar mechanisms.

Decreased extracellular volume also induces release of vasopressin from the hypothalamus. In the kidney collecting duct, vasopressin binds to V2 receptors at the basolateral membrane, which increases Na⁺ transport through a pathway that includes cAMP and protein kinase A (PKA) (19). This pathway increases Na⁺ transport more quickly than aldosterone (minutes) because it does not depend on de novo protein synthesis. Both aldosterone and vasopressin increase Na⁺ transport at least in part by altering ENaC trafficking to and from the cell surface (27, 28, 29), as described in the following sections.

	Aldosterone Controls Endoplasmic Reticulum (ER) Export by Regulating ENaC Transcription

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Individual ENaC subunits are capable of trafficking from the ER to the cell surface, but this process is inefficient (30, 31, 32, 33). Efficient trafficking of ENaC out of the ER requires assembly of the -, ß-, and -subunits into a complex. Under basal conditions in the kidney, when the rate of Na⁺ transport is low, ENaC is transcribed to a lesser extent than ß or ENaC (Fig. 2) (34, 35, 36, 37, 38). Excess ß- and -subunits are targeted for degradation in the proteasome (32, 39). Thus, ENaC trafficking out of the ER is limited by the number of available -subunits. This bottleneck forms an important site for ENaC regulation. Aldosterone increases ENaC transcription (but not ß- and ENaC) (34, 35, 36, 37, 38), resulting in enhanced channel assembly and trafficking from the ER to the plasma membrane (Fig. 2). As a result, aldosterone increases Na⁺ transport. Interestingly, this noncoordinate transcription is tissue-specific. For example, in rat colon, aldosterone increases ß- and ENaC transcription to a much greater extent than ENaC (34, 36, 37). Moreover, recent work using a renal collecting duct cell line (M1) suggested that expression of ENaC might limit formation of function channels; overexpression of ENaC was sufficient to increase Na⁺ transport (40).

View larger version (30K): [in this window] [in a new window]   FIG. 2. Model of ENaC trafficking. Aldosterone stimulates transcription of ENaC (in kidney collecting duct), resulting in formation of functional channel complexes, which facilitates ENaC release from the ER. In the Golgi, some ENaC channels are proteolytically cleaved in the extracellular domain of - and ENaC, resulting in channel activation. At the cell surface, Nedd4-2 binds to ENaC, increasing endocytosis and degradation. This step likely involves ubiquitination of N-terminal lysines in - and ENaC. SGK and PKA inhibit endocytosis and degradation by phosphorylating Nedd4-2, which decreases Nedd4-2 binding to ENaC.

	Proteolytic Cleavage of ENaC in the Golgi Activates ENaC

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Recent work suggests that ENaC is synthesized and transported from the ER to Golgi in an inactive form. In the Golgi, furin proteolytically cleaves specific sites in the extracellular domains of the - and -subunits (Figs. 1 and 2) (42). This cleavage appears to activate ENaC, converting electrically near-silent channels (P_O approximately 0.02) into channels that are capable of transporting Na⁺ (P_O approximately 0.6) (43). In this regard, ENaC maturation is similar to some hormones and proteases, which undergo proteolytic processing from proproteins to active forms. One might speculate that such a mechanism may protect intracellular compartments from the potential toxic effects of a constitutively active Na⁺ channel. A fraction of ENaC channels escape cleavage during transport to the cell surface, possibly via a route that bypasses the Golgi (44). This inactive pool can subsequently be cleaved and activated by extracellular or membrane-tethered serine proteases, including trypsin (45), channel-activating proteases 1–3 (46, 47), TMPRSS3 (48), and neutrophil elastase (49). The mechanism by which cleavage activates ENaC is unknown, although it may do so in part by relieving the channel from inhibition by extracellular Na⁺ (Na⁺ self-inhibition) (50). It is also not known whether ENaC cleavage is regulated or whether it is a constitutive step in channel maturation.

	ENaC Exocytosis

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Little is known about the mechanisms involved in ENaC trafficking to the cell surface. Previous work reported that expression of syntaxins 1 and 3 alter ENaC current (51, 52). Thus, by analogy to other systems, it seems likely that syntaxins and other SNARE proteins mediate ENaC exocytosis. However, ENaC trafficking may by unique in that it appears to involve a direct physical interaction between cargo (ENaC) and syntaxins (53, 54). In addition to its effect on ENaC trafficking, syntaxin 1A has also been reported to inhibit ENaC by altering its gating (55).

ENaC exocytosis is increased by cAMP (Fig. 2) (28, 56). This is one of the pathways by which vasopressin regulates Na⁺ transport, similar to regulation of epithelial water transport via cAMP-mediated stimulation of aquaporin 2 exocytosis (57). Although the underlying mechanisms have not been identified, this raises the possibility of coordinate regulation of ENaC and aquaporin 2 to respond to conditions of volume depletion. The ENaC channels responsive to cAMP are derived in part from a recycling pool of channels (Fig. 2) (56), although it is likely that a pool of newly synthesized channels also contributes (28).

	C-Terminal Sequence Controls ENaC Stability at the Cell Surface

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
ENaC surface expression is controlled by a sequence (PPPXYXXL) conserved in the C terminus of -, ß-, and ENaC (Fig. 1) (58, 59). Missense mutations or deletion of this sequence increase ENaC surface expression (30, 58), causing Liddle’s syndrome, an inherited form of hypertension characterized by excessive renal Na⁺ reabsorption (60, 61, 62, 63). Two mechanisms have been proposed to explain this increase in ENaC surface expression. First, the PPPXYXXL sequence is similar to two endocytosis motifs, NPXY and YXXø, suggesting that this sequence might mediate ENaC endocytosis (58, 64). Consistent with this hypothesis, deletion of this motif decreased the rate of ENaC current decay after treatment of cells with brefeldin A (to block exocytosis) (40, 64). Moreover, a dominant negative dynamin (to block endocytosis) increased ENaC current (64), consistent with a role for clathrin-mediated endocytosis in the control of ENaC surface expression. Second, the PPPXYXXL sequence fits the consensus of a PY motif (PPXY), a sequence involved in protein interactions. The ENaC PY motifs function as a binding site for members of the Nedd4 family of E3 ubiquitin-protein ligases (65, 66, 67, 68, 69).

	Nedd4-2 Targets ENaC for Degradation

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Nedd4 and related E3 ubiquitin-protein ligases contain three to four WW domains that bind to PY motifs in -, ß-, and ENaC (Fig. 2) (65, 68, 69, 70, 71, 72, 73, 74, 75, 76). The binding of Nedd4 family members decreases Na⁺ current by reducing ENaC expression at the cell surface (66, 77). Although several family members are capable of inhibiting ENaC in heterologous cells (66, 69, 77, 78, 79), recent work suggests that Nedd4-2 (also referred to as Nedd4L) is most important for ENaC regulation in vivo (80). A number of findings suggest that Nedd4-2 inhibits ENaC via ubiquitination of one of more ENaC subunits. First, Nedd4-2 (and Nedd4 family members) contain a HECT (homologous to the E6-AP carboxyl terminus) ubiquitin ligase domain (Fig. 2), which is required for Nedd4-2 to inhibit ENaC (66, 77). Second, lysines at the N terminus of - and ENaC are ubiquitinated (Figs. 1 and 2), resulting in decreased ENaC current (39). Conversely, inhibitors of the proteasome and lysosomes increase ENaC protein and current (39, 81). Finally, Nedd4 (and presumably Nedd4-2) increases the rate of ENaC degradation (Fig. 2) (66), consistent with a role for ubiquitination. It seems likely that ubiquitination might also increase ENaC endocytosis, as described for some membrane proteins (Fig. 2) (82), although this hypothesis remains unproven. However, despite these data, direct evidence that Nedd4-2 (or related proteins) ubiquitinate ENaC is lacking. It remains a possibility that Nedd4-2 regulates ENaC indirectly through ubiquitination of an associated protein, similar to endocytosis of the ß2-adrenergic receptor in response to ubiquitination of ß-arrestin (83).

A number of Nedd4-2 splice variants have been identified (84, 85, 86). Some lack one or more WW domain, which disrupts Nedd4-2 function when expressed in heterologous cells (86). Another isoform contains an N-terminal calcium-phospholipid binding (C2) domain; surprisingly, this domain does not seem to alter Nedd4-2 function (72, 85). A naturally occurring Nedd4-2 sequence variant (P355L) has also been identified that produces a subtle decrease in Nedd4-2 activity (87). Although the physiological role of Nedd4-2 splice variants and sequence variants is not yet known, an association has been reported between postural change in systolic blood pressure and a Nedd4-2 variant predicted to produce a nonfunctional protein (variant 13) (88). Thus, it seems possible that genetic variation in Nedd4-2 could contribute to blood pressure variation in humans.

	Nedd4-2 Is Regulated by Phosphorylation

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
Because Nedd4-2 targets ENaC for degradation, it plays an important role under conditions when it is necessary to minimize Na⁺ transport, such as in response to excess Na⁺ intake. In contrast, ENaC surface expression must increase to maximize Na⁺ transport under conditions of Na⁺ deprivation. Aldosterone and vasopressin are the principal mediators of this response. Both pathways converge on Nedd4-2; serum and glucocorticoid-induced kinase (SGK) and PKA, downstream mediators of aldosterone and vasopressin, respectively, phosphorylate a common set of three Nedd4-2 Ser/Thr residues (Ser-221, Thr-246, and Ser-327; Fig. 3) (89, 90, 91). Phosphorylation inhibits Nedd4-2 by blocking its binding to ENaC. As a result, ENaC surface expression and, hence, Na⁺ transport, are increased. In its phosphorylated form, Nedd4-2 ubiquitinates SGK, inducing SGK degradation (Fig. 3) (92). This may function as a negative feedback mechanism to limit to extent and duration of signaling through the aldosterone-SGK- Nedd4-2 pathway. Nedd4-2 may also be a convergence point for insulin to regulate epithelial Na⁺ transport; through its activation of the PI-3 kinase pathway, insulin induces SGK phosphorylation, which is required for SGK activity (93, 94).

View larger version (16K): [in this window] [in a new window]   FIG. 3. Convergent regulation of ENaC trafficking via Nedd4-2. Aldosterone and vasopressin activate pathways that culminate in phosphorylation of Nedd4-2 by SGK and PKA. Phosphorylation blocks Nedd4-2 binding to ENaC, possibly through an interaction between phospho-Nedd4-2 and 14-3-3 proteins. This negative regulation of Nedd4-2 increases ENaC surface expression.

The binding of Nedd4-2 to ENaC might also be regulated by ENaC phosphorylation. Phosphorylation of two residues adjacent to the PY motifs (Thr-613 in ßENaC and Thr-623 in ENaC) by ERK increased binding of ENaC peptides to WW domains derived from Nedd4, a Nedd4-2 relative (96). Additional work is required to determine whether ENaC phosphorylation by ERK or other kinases alters binding to Nedd4-2 and to investigate the physiological relevance of ENaC phosphorylation in vivo.

	Additional Regulators of ENaC Surface Expression

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
ENaC surface expression is altered by a variety of additional signaling molecules and proteins, although the mechanistic details remain under investigation. Some examples include arachidonic acid analogs (97), AMP-activated kinase (98), and protein kinase C (99), which decrease ENaC surface expression. Conversely, phosphatidylinositol 4,5-bisphosphate may increase ENaC surface expression through a pathway that includes RhoA, Rho kinase, and phosphatidylinositol 4-phosphate 5-kinase (100). Surface expression is also increased by IB kinase-ß (101). In addition to the PY motifs that bind Nedd4-2, other ENaC domains may also participate in ENaC trafficking, including sequences in ENaC at the N terminus (102) and in the C terminus close to the second membrane-spanning segment (103). Sequence variations in ENaC also alter its surface expression (in addition to Liddle’s syndrome mutations discussed earlier). Mutation of a conserved cysteine in the extracellular domain of ENaC (C133Y) decreases ENaC trafficking to the cell surface (104), one of the causes of pseudohypoaldosteronism Type I, an inherited disorder of severe Na⁺ wasting and hypotension. A common variant in the C terminus of ENaC (T663A) produces a more subtle decrease in ENaC surface expression (105), although its physiological significance remains uncertain (106). Additional work is required to determine the mechanisms by which these pathways and sequence variations alter ENaC trafficking.

	Conclusion

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 
ENaC regulation is critical to maintain a fine balance between Na⁺ depletion and Na⁺ excess. Defects in this regulation cause diseases including Liddle’s syndrome and other rare inherited forms of hypertension. As a logical extension of this work, these disorders may serve as a paradigm to understand more common forms of hypertension (essential hypertension). It seems likely that genetic variation in ENaC and its regulatory proteins contributes to blood pressure variation in the population; some variants may predispose to hypertension, whereas others may protect against hypertension. Thus, identification of the molecules and pathways that regulate ENaC trafficking may provide new insights into the pathogenesis of hypertension and other disorders of Na⁺ homeostasis.

	Acknowledgments

 
I thank my laboratory colleagues for their input and participation in many of the studies described in this review.

	Footnotes

 
This work was supported by National Heart, Lung, and Blood Institute Grants HL58812, HL72256, and HL55006 and by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK52617 (National Institutes of Health).

First Published Online September 8, 2005

Abbreviations: ENaC, Epithelial Na⁺ channel; ER, endoplasmic reticulum; PKA, protein kinase A; SGK, serum and glucocorticoid-induced kinase.

Received July 18, 2005.

Accepted for publication August 31, 2005.

	References

Top Abstract Introduction ENaC in Epithelial Na+... Hormonal Regulation of ENaC Aldosterone Controls Endoplasmic... Proteolytic Cleavage of ENaC... ENaC Exocytosis C-Terminal Sequence Controls... Nedd4-2 Targets ENaC for... Nedd4-2 Is Regulated by... Additional Regulators of ENaC... Conclusion References

 

1. Lifton RP, Wilson FH, Choate KA, Geller DS 2002 Salt and blood pressure: new insight from human genetic studies. Cold Spring Harb Symp Quant Biol 67:445–450[CrossRef][Medline]
2. Canessa CM, Horisberger JD, Rossier BC 1993 Epithelial sodium channel related to proteins involved in neurodegeneration. Nature 361:467–470[CrossRef][Medline]
3. Lingueglia E, Voilley N, Waldmann R, Lazdunski M, Barbry P 1993 Expression cloning of an epithelial amiloride-sensitive Na⁺ channel. A new channel type with homologies to Caenorhabditis elegans degenerins. FEBS Lett 318:95–99[CrossRef][Medline]
4. 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 367:463–467[CrossRef][Medline]
5. McDonald FJ, Snyder PM, McCray Jr PB, Welsh MJ 1994 Cloning, expression, and tissue distribution of a human amiloride-sensitive Na⁺ channel. Am J Physiol 266:L728–L734
6. McDonald FJ, Price MP, Snyder PM, Welsh MJ 1995 Cloning and expression of the ß- and -subunits of the human epithelial sodium channel. Am J Physiol 268:C1157–C1163
7. Voilley N, Lingueglia E, Champigny G, Mattei MG, Waldmann R, Lazdunski M, Barbry P 1994 The lung amiloride-sensitive Na⁺ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning. Proc Natl Acad Sci USA 91:247–251[Abstract/Free Full Text]
8. Renard S, Lingueglia E, Voilley N, Lazdunski M, Barbry P 1994 Biochemical analysis of the membrane topology of the amiloride-sensitive Na⁺ channel. J Biol Chem 269:12981–12986[Abstract/Free Full Text]
9. Snyder PM, McDonald FJ, Stokes JB, Welsh MJ 1994 Membrane topology of the amiloride-sensitive epithelial sodium channel. J Biol Chem 269:24379–24383[Abstract/Free Full Text]
10. Canessa CM, Merillat AM, Rossier BC 1994 Membrane topology of the epithelial sodium channel in intact cells. Am J Physiol 267:C1682–C1690
11. Snyder PM, Cheng C, Prince LS, Rogers JC, Welsh MJ 1998 Electrophysiological and biochemical evidence that DEG/ENaC cation channels are composed of nine subunits. J Biol Chem 273:681–684[Abstract/Free Full Text]
12. Firsov D, Gautschi I, Merillat AM, Rossier BC, Schild L 1998 The heterotetrameric architecture of the epithelial sodium channel (ENaC). EMBO J 17:344–352[CrossRef][Medline]
13. Kosari F, Sheng S, Li J, Mak DO, Foskett JK, Kleyman TR 1998 Subunit stoichiometry of the epithelial sodium channel. J Biol Chem 273:13469–13474[Abstract/Free Full Text]
14. Eskandari S, Snyder PM, Kreman M, Zampighi GA, Welsh MJ, Wright EM 1999 Number of subunits comprising the epithelial sodium channel. J Biol Chem 274:27281–27286[Abstract/Free Full Text]
15. Staruschenko A, Medina JL, Patel P, Shapiro MS, Booth RE, Stockand JD 2004 Fluorescence resonance energy transfer analysis of subunit stoichiometry of the epithelial Na⁺ channel. J Biol Chem 279:27729–27734[Abstract/Free Full Text]
16. Staruschenko A, Adams E, Booth RE, Stockand JD 2005 Epithelial Na⁺ channel subunit stoichiometry. Biophys J 88:3966–3975[Abstract/Free Full Text]
17. Garty H, Palmer LG 1997 Epithelial sodium channels: function, structure, and regulation. Physiol Rev 77:359–396[Abstract/Free Full Text]
18. Benos DJ, Fuller CM, Shlyonsky VG, Berdiev BK, Ismailov II 1997 Amiloride-sensitive Na⁺ channels: insights and outlooks. News Phys Sci 12:55–61[Abstract/Free Full Text]
19. Schafer JA 2002 Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. Am J Physiol Renal Physiol 283:F221–F235
20. 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 -ENaC-deficient mice. Nat Genet 12:325–328[CrossRef][Medline]
21. O’Brodovich H 2001 Fetal lung liquid secretion: insights using the tools of inhibitors and genetic knock-out experiments. Am J Respir Cell Mol Biol 25:8–10[Free Full Text]
22. Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC 2004 Increased airway epithelial Na⁺ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 10:487–493[CrossRef][Medline]
23. Smith JJ, Travis SM, Greenberg EP, Welsh MJ 1996 Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 85:229–236[CrossRef][Medline]
24. Zabner J, Smith JJ, Karp PH, Widdicombe JH, Welsh MJ 1998 Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell 2:397–403[CrossRef][Medline]
25. Stokes JB 1999 Disorders of the epithelial sodium channel: insights into the regulation of extracellular volume and blood pressure. Kidney Int 56:2318–2333[CrossRef][Medline]
26. Stockand JD 2002 New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282:F559–F576
27. Loffing J, Zecevic M, Feraille E, Kaissling B, Asher C, Rossier BC, Firestone GL, Pearce D, Verrey F 2001 Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK. Am J Physiol Renal Physiol 280:F675–F682
28. Snyder PM 2000 Liddle’s syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na⁺ channel to the cell surface. J Clin Invest 105:45–53[Medline]
29. 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 120:71–85[Abstract/Free Full Text]
30. Firsov D, Schild L, Gautschi I, Merillat AM, Schneeberger E, Rossier BC 1996 Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach. Proc Natl Acad Sci USA 93:15370–15375[Abstract/Free Full Text]
31. Prince LS, Welsh MJ 1998 Cell surface expression and biosynthesis of epithelial Na⁺ channels. Biochem J 336:705–710
32. Valentijn JA, Fyfe GK, Canessa CM 1998 Biosynthesis and processing of epithelial sodium channels in Xenopus oocytes. J Biol Chem 273:30344–30351[Abstract/Free Full Text]
33. Weisz OA, Wang JM, Edinger RS, Johnson JP 2000 Non-coordinate regulation of endogenous epithelial sodium channel (ENaC) subunit expression at the apical membrane of A6 cells in response to various transporting conditions. J Biol Chem 275:39886–39893[Abstract/Free Full Text]
34. Stokes JB, Sigmund RD 1998 Regulation of rENaC mRNA by dietary NaCl and steroids: organ, tissue, and steroid heterogeneity. Am J Physiol 274:C1699–C1707
35. Ono S, Kusano E, Muto S, Ando Y, Asano Y 1997 A low-Na⁺ diet enhances expression of mRNA for epithelial Na⁺ channel in rat renal inner medulla. Pflugers Arch 434:756–763[CrossRef][Medline]
36. Asher C, Wald H, Rossier BC, Garty H 1996 Aldosterone-induced increase in the abundance of Na⁺ channel subunits. Am J Physiol 271:C605–C611
37. Escoubet B, Coureau C, Bonvalet JP, Farman N 1997 Noncoordinate regulation of epithelial Na channel and Na pump subunit mRNAs in kidney and colon by aldosterone. Am J Physiol 272:C1482–C1491
38. Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA 1999 Aldosterone-mediated regulation of ENaC , ß, and subunit proteins in rat kidney. J Clin Invest 104:R19–R23
39. Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D 1997 Regulation of stability and function of the epithelial Na⁺ channel (ENaC) by ubiquitination. EMBO J 16:6325–6336[CrossRef][Medline]
40. Volk KA, Husted RF, Sigmund RD, Stokes JB 2005 Overexpression of the epithelial Na⁺ channel subunit in collecting duct cells: interactions of Liddle’s mutations and steroids on expression and function. J Biol Chem 280:18348–18354[Abstract/Free Full Text]
41. Zerangue N, Schwappach B, Jan YN, Jan LY 1999 A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron 22:537–548[CrossRef][Medline]
42. Hughey RP, Bruns JB, Kinlough CL, Harkleroad KL, Tong Q, Carattino MD, Johnson JP, Stockand JD, Kleyman TR 2004 Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 279:18111–18114[Abstract/Free Full Text]
43. Caldwell RA, Boucher RC, Stutts MJ 2004 Serine protease activation of near-silent epithelial Na⁺ channels. Am J Physiol Cell Physiol 286:C190–C194
44. Hughey RP, Bruns JB, Kinlough CL, Kleyman TR 2004 Distinct pools of epithelial sodium channels are expressed at the plasma membrane. J Biol Chem 279:48491–48494[Abstract/Free Full Text]
45. Chraibi A, Vallet V, Firsov D, Hess SK, Horisberger JD 1998 Protease modulation of the activity of the epithelial sodium channel expressed in Xenopus oocytes. J Gen Physiol 111:127–138[Abstract/Free Full Text]
46. Vallet V, Chraibi A, Gaeggeler HP, Horisberger JD, Rossier BC 1997 An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 389:607–610[CrossRef][Medline]
47. Vuagniaux G, Vallet V, Jaeger NF, Hummler E, Rossier BC 2002 Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol 120:191–201[Abstract/Free Full Text]
48. Guipponi M, Vuagniaux G, Wattenhofer M, Shibuya K, Vazquez M, Dougherty L, Scamuffa N, Guida E, Okui M, Rossier C, Hancock M, Buchet K, Reymond A, Hummler E, Marzella PL, Kudoh J, Shimizu N, Scott HS, Antonarakis SE, Rossier BC 2002 The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet 11:2829–2836[Abstract/Free Full Text]
49. Caldwell RA, Boucher RC, Stutts MJ 2005 Neutrophil elastase activates near-silent epithelial Na⁺ channels and increases airway epithelial Na⁺ transport. Am J Physiol Lung Cell Mol Physiol 288:L813–L819
50. Chraibi A, Horisberger JD 2002 Na self inhibition of human epithelial Na channel: temperature dependence and effect of extracellular proteases. J Gen Physiol 120:133–145[Abstract/Free Full Text]
51. Saxena S, Quick MW, Tousson A, Oh Y, Warnock DG 1999 Interaction of syntaxins with the amiloride-sensitive epithelial sodium channel. J Biol Chem 274:20812–20817[Abstract/Free Full Text]
52. Qi J, Peters KW, Liu C, Wang JM, Edinger RS, Johnson JP, Watkins SC, Frizzell RA 1999 Regulation of the amiloride-sensitive epithelial sodium channel by syntaxin 1A. J Biol Chem 274:30345–30348[Abstract/Free Full Text]
53. Condliffe SB, Carattino MD, Frizzell RA, Zhang H 2003 Syntaxin 1A regulates ENaC via domain-specific interactions. J Biol Chem 278:12796–12804[Abstract/Free Full Text]
54. Berdiev BK, Jovov B, Tucker WC, Naren AP, Fuller CM, Chapman ER, Benos DJ 2004 ENaC subunit-subunit interactions and inhibition by syntaxin 1A. Am J Physiol Renal Physiol 286:F1100–F1106
55. Condliffe SB, Zhang H, Frizzell RA 2004 Syntaxin 1A regulates ENaC channel activity. J Biol Chem 279:10085–10092[Abstract/Free Full Text]
56. Butterworth MB, Edinger RS, Johnson JP, Frizzell RA 2005 Acute ENaC stimulation by cAMP in a kidney cell line is mediated by exocytic insertion from a recycling channel pool. J Gen Physiol 125:81–101[Abstract/Free Full Text]
57. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA 1995 Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA 92:1013–1017[Abstract/Free Full Text]
58. Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ 1995 Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na⁺ channel. Cell 83:969–978[CrossRef][Medline]
59. Schild L, Lu Y, Gautschi I, Schneeberger E, Lifton RP, Rossier BC 1996 Identification of a PY motif in the epithelial Na⁺ channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. EMBO J 15:2381–2387[Medline]
60. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill Jr JR, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Lifton RP 1994 Liddle’s syndrome: heritable human hypertension caused by mutations in the ß subunit of the epithelial sodium channel. Cell 79:407–414[CrossRef][Medline]
61. Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP 1995 Hypertension caused by a truncated epithelial sodium channel subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 11:76–82[CrossRef][Medline]
62. Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP 1995 A de novo missense mutation of the ß subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci USA 92:11495–11499[Abstract/Free Full Text]
63. Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC 1996 Liddle disease caused by a missense mutation of ß subunit of the epithelial sodium channel gene. J Clin Invest 97:1780–1784[Medline]
64. Shimkets RA, Lifton RP, Canessa CM 1997 The activity of the epithelial sodium channel is regulated by clathrin-mediated endocytosis. J Biol Chem 272:25537–25541[Abstract/Free Full Text]
65. 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 15:2371–2380[Medline]
66. Goulet CC, Volk KA, Adams CM, Prince LS, Stokes JB, Snyder PM 1998 Inhibition of the epithelial Na⁺ channel by interaction of Nedd4 with a PY motif deleted in Liddle’s syndrome. J Biol Chem 273:30012–30017[Abstract/Free Full Text]
67. Kamynina E, Debonneville C, Bens M, Vandewalle A, Staub O 2001 A novel mouse Nedd4 protein suppresses the activity of the epithelial Na⁺ channel. FASEB J 15:204–214[Abstract/Free Full Text]
68. Harvey KF, Dinudom A, Cook DI, Kumar S 2001 The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J Biol Chem 276:8597–8601[Abstract/Free Full Text]
69. McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM 2002 Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na⁽⁺⁾ channel. Am J Physiol Renal Physiol 283:F431–F436
70. Harvey KF, Dinudom A, Komwatana P, Jolliffe CN, Day ML, Parasivam G, Cook DI, Kumar S 1999 All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na⁺. J Biol Chem 274:12525–12530[Abstract/Free Full Text]
71. Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ 2000 Human Nedd4 interacts with the human epithelial Na⁺ channel: WW3 but not WW1 binds to Na⁺-channel subunits. Biochem J 345:503–509
72. Snyder PM, Olson DR, McDonald FJ, Bucher DB 2001 Multiple WW domains, but not the C2 domain, are required for the inhibition of ENaC by human Nedd4. J Biol Chem 276:28321–28326[Abstract/Free Full Text]
73. Asher C, Chigaev A, Garty H 2001 Characterization of interactions between Nedd4 and ß and ENaC using surface plasmon resonance. Biochem Biophys Res Commun 286:1228–1231[CrossRef][Medline]
74. Kanelis V, Rotin D, Forman-Kay JD 2001 Solution structure of a Nedd4 WW domain-ENaC peptide complex. Nat Struct Biol 8:407–412[CrossRef][Medline]
75. Lott JS, Coddington-Lawson SJ, Teesdale-Spittle PH, McDonald FJ 2002 A single WW domain is the predominant mediator of the interaction between the human ubiquitin-protein ligase Nedd4 and the human epithelial sodium channel. Biochem J 361:481–488[CrossRef][Medline]
76. Fotia AB, Dinudom A, Shearwin KE, Koch JP, Korbmacher C, Cook DI, Kumar S 2003 The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB J 17:70–72[Abstract/Free Full Text]
77. Abriel H, Loffing J, Rebhun JF, Pratt JH, Schild L, Horisberger JD, Rotin D, Staub O 1999 Defective regulation of the epithelial Na⁺ channel by Nedd4 in Liddle’s syndrome. J Clin Invest 103:667–673[Medline]
78. Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, Cook DI 1998 Nedd4 mediates control of an epithelial Na⁺ channel in salivary duct cells by cytosolic Na⁺. Proc Natl Acad Sci USA 95:7169–7173[Abstract/Free Full Text]
79. Kamynina E, Tauxe C, Staub O 2001 Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na⁽⁺⁾ channel regulation. Am J Physiol Renal Physiol 281:F469–F477
80. Snyder PM, Steines JC, Olson DR 2004 Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference. J Biol Chem 279:5042–5046[Abstract/Free Full Text]
81. Malik B, Schlanger L, Al-Khalili O, Bao HF, Yue G, Price SR, Mitch WE, Eaton DC 2001 ENac degradation in A6 cells by the ubiquitin-proteosome proteolytic pathway. J Biol Chem 276:12903–12910[Abstract/Free Full Text]
82. Hicke L 1997 Ubiquitin-dependent internalization and down-regulation of plasma membrane proteins. FASEB J 11:1215–1226[Abstract]
83. Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ 2001 Regulation of receptor fate by ubiquitination of activated ß2-adrenergic receptor and ß-arrestin. Science 294:1307–1313[Abstract/Free Full Text]
84. Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, Leppert MF, Lalouel JM, Weiss RB 2002 Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript. J Hum Genet 47:665–676[CrossRef][Medline]
85. Itani OA, Campbell JR, Herrero J, Snyder PM, Thomas CP 2003 Alternate promoters and variable splicing lead to hNedd4-2 isoforms with a C2 domain and varying number of WW domains. Am J Physiol Renal Physiol 285:F916–F929
86. Itani OA, Stokes JB, Thomas CP 2005 Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. Am J Physiol Renal Physiol 289:F334–F346
87. Fouladkou F, Alikhani-Koopaei R, Vogt B, Flores SY, Malbert-Colas L, Lecomte MC, Loffing J, Frey FJ, Frey BM, Staub O 2004 A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation due to differential phosphorylation of Nedd4-2 in Xenopus laevis oocytes. Am J Physiol Renal Physiol 287:F550–F561
88. Pankow JS, Dunn DM, Hunt SC, Leppert MF, Miller MB, Rao DC, Heiss G, Oberman A, Lalouel JM, Weiss RB 2005 Further evidence of a quantitative trait locus on chromosome 18 influencing postural change in systolic blood pressure: the Hypertension Genetic Epidemiology Network (HyperGEN) Study. Am J Hypertens 18:672–678[CrossRef][Medline]
89. Snyder PM, Olson DR, Thomas BC 2002 Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of ENaC. J Biol Chem 277:5–8[Abstract/Free Full Text]
90. Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Munster C, Chraibi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, Staub O 2001 Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na⁽⁺⁾ channel cell surface expression. EMBO J 20:7052–7059[CrossRef][Medline]
91. Snyder PM, Olson DR, Kabra R, Zhou R, Steines JC 2004 cAMP and SGK regulate ENaC through convergent phosphorylation of Nedd4-2. J Biol Chem 279:45753–45758[Abstract/Free Full Text]
92. Zhou R, Snyder PM 2005 Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem 280:4518–4523[Abstract/Free Full Text]
93. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA 1999 Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 18:3024–3033[CrossRef][Medline]
94. Wang J, Barbry P, Maiyar AC, Rozansky DJ, Bhargava A, Leong M, Firestone GL, Pearce D 2001 SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport. Am J Physiol Renal Physiol 280:F303–F313
95. Ichimura T, Yamamura H, Sasamoto K, Tominaga Y, Taoka M, Kakiuchi K, Shinkawa T, Takahashi N, Shimada S, Isobe T 2005 14-3-3 Proteins modulate the expression of epithelial Na⁺ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. J Biol Chem 280:13187–13194[Abstract/Free Full Text]
96. Shi H, Asher C, Chigaev A, Yung Y, Reuveny E, Seger R, Garty H 2002 Interactions of ß and ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation. J Biol Chem 277:13539–13547[Abstract/Free Full Text]
97. Carattino MD, Hill WG, Kleyman TR 2003 Arachidonic acid regulates surface expression of epithelial sodium channels. J Biol Chem 278:36202–36213[Abstract/Free Full Text]
98. Carattino MD, Edinger RS, Grieser HJ, Wise R, Neumann D, Schlattner U, Johnson JP, Kleyman TR, Hallows KR 2005 Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. J Biol Chem 280:17608–17616[Abstract/Free Full Text]
99. Booth RE, Stockand JD 2003 Targeted degradation of ENaC in response to PKC activation of the ERK1/2 cascade. Am J Physiol Renal Physiol 284:F938–F947
100. Staruschenko A, Nichols A, Medina JL, Camacho P, Zheleznova NN, Stockand JD 2004 Rho small GTPases activate the epithelial Na⁽⁺⁾ channel. J Biol Chem 279:49989–49994[Abstract/Free Full Text]
101. Lebowitz J, Edinger RS, An B, Perry CJ, Onate S, Kleyman TR, Johnson JP 2004 Ib kinase-ß (ikkß) modulation of epithelial sodium channel activity. J Biol Chem 279:41985–41990[Abstract/Free Full Text]
102. Chalfant ML, Denton JS, Langloh AL, Karlson KH, Loffing J, Benos DJ, Stanton BA 1999 The NH(2) terminus of the epithelial sodium channel contains an endocytic motif. J Biol Chem 274:32889–32896[Abstract/Free Full Text]
103. Volk KA, Snyder PM, Stokes JB 2001 Regulation of epithelial Na channel activity through a region of the carboxy terminus of the -subunit. Evidence for intracellular kinase mediated reactions. J Biol Chem 276:43887–43893[Abstract/Free Full Text]
104. Firsov D, Robert-Nicoud M, Gruender S, Schild L, Rossier BC 1999 Mutational analysis of cysteine-rich domains of the epithelium sodium channel (ENaC). Identification of cysteines essential for channel expression at the cell surface. J Biol Chem 274:2743–2749[Abstract/Free Full Text]
105. Samaha FF, Rubenstein RC, Yan W, Ramkumar M, Levy DI, Ahn YJ, Sheng S, Kleyman TR 2004 Functional polymorphism in the carboxyl terminus of the -subunit of the human epithelial sodium channel. J Biol Chem 279:23900–23907[Abstract/Free Full Text]
106. Ambrosius WT, Bloem LJ, Zhou L, Rebhun JF, Snyder PM, Wagner MA, Guo C, Pratt JH 1999 Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension. Hypertension 34:631–637[Abstract/Free Full Text]

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