Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P41181 (collecting duct)
5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liddle's syndrome is a form of inherited hypertension linked to mutations in the genes encoding the epithelial Na+ channel (ENaC). These mutations alter or delete PY motifs involved in protein-protein interactions with a ubiquitin-protein ligase, Nedd4. Here we show that Na+ transporting cells, derived from mouse cortical collecting duct, express two Nedd4 proteins with different structural organization and characteristics of ENaC regulation: 1) the classical Nedd4 (herein referred to as Nedd4-1) containing one amino-terminal C2, three WW, and one HECT-ubiquitin protein ligase domain and 2) a novel Nedd4 protein (Nedd4-2), homologous to Xenopus Nedd4 and comprising four WW, one HECT, yet lacking a C2 domain. Nedd4-2, but not Nedd4-1, inhibits ENaC activity when coexpressed in Xenopus oocytes and this property correlates with the ability to bind to ENaC, as only Nedd4-2 coimmunoprecipitates with ENaC. Furthermore, this interaction depends on the presence of at least one PY motif in the ENaC complex and on WW domains 3 and 4 in Nedd4-2. Thus, these results suggest that the novel suppressor protein Nedd4-2 is the regulator of ENaC and hence a potential susceptibility gene for arterial hypertension.
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PMID:A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. 1114 8

The epithelial Na(+) channel (ENaC), which plays an essential role in renal Na(+) handling, is composed of three subunits (alpha beta gamma), each containing a conserved PY motif at the C terminus. In Liddle's syndrome, an inherited form of salt-sensitive hypertension, the PY motifs of either beta or gamma ENaC are deleted or modified. We have recently shown that a ubiquitin-protein ligase Nedd4 binds via its WW domains to these PY motifs on ENaC, that ENaC is regulated by ubiquitination, and that Xenopus laevis Nedd4 (xNedd4) controls the cell surface pool of ENaC when coexpressed in Xenopus oocytes. Interestingly, Na(+) transporting cells, derived from mouse cortical collecting duct, express two different Nedd4 isoforms, which we have termed mNedd4-1 and mNedd4-2. Only mNedd4-2, which is orthologous to xNedd4, but not mNedd4-1, is able to regulate ENaC activity, and this property correlates with the capability to bind to the ENaC complex. Hence, Nedd4-2 may be encoded by a novel susceptibility gene for arterial hypertension.
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PMID:Liddle's syndrome: a novel mouse Nedd4 isoform regulates the activity of the epithelial Na(+) channel. 1147 28

The epithelial Na+ channel (ENaC) forms the pathway for Na+ absorption across epithelia, including the kidney collecting duct, where it plays a critical role in Na+ homeostasis and blood pressure control. Na+ absorption is regulated in part by mechanisms that control the expression of ENaC at the apical cell surface. Nedd4 family members (e.g. Nedd4, Nedd4-2) bind to the channel and decrease its surface expression by catalyzing its ubiquitination and degradation. Conversely, serum and glucocorticoid-regulated kinase (SGK), a downstream mediator of aldosterone, increases the expression of ENaC at the cell surface. Here we show that SGK and human Nedd4-2 (hNedd4-2) converge in a common pathway to regulate epithelial Na+ absorption. Consistent with this model, we found that SGK bound to hNedd4-2 and hNedd4. A PY motif in SGK mediated the interaction and was required for SGK to stimulate ENaC. SGK phosphorylated hNedd4-2 (but not hNedd4), altering hNedd4-2 function; phosphorylation reduced the binding of hNedd4-2 to alphaENaC, and hence, the hNedd4-2-mediated inhibition of Na+ absorption. These data suggest that SGK regulates epithelial Na+ absorption in part by modulating the function of hNedd4-2.
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PMID:Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. 1169 33

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPXY motif that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the beta or gamma subunits, has been shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.
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PMID:Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. 1205 Jan 53

Mutations that disrupt a PY motif in epithelial Na+ channel (ENaC) subunits increase surface expression of Na+ channels in the collecting duct, resulting in greater Na+ reabsorption. Recently, Nedd4 and Nedd4-2 have been identified as ubiquitin ligases that can interact with ENaC via its PY motifs to regulate channel activity. To further understand the role of human Nedd4-2 (hNedd4-2), we cloned its cDNAs and determined its genomic organization using a bioinformatic approach. The gene is present as a single copy, spans at least 400 kb, and contains >40 exons. Multiple 5'-exons were identified by 5'-rapid amplification of cDNA ends, and tissue-specific expression of these transcripts was noted by RT-PCR and RNase protection assay. Alternate polyadenylation signal sequences led to varying lengths of the 3'-untranslated region. Alternate splicing events within internal exons were also noted. Open reading frame analysis indicates that hNedd4-2 encode multiple protein variants with and without a C2 domain, and with a variable number of WW domains. Coexpression, in Fischer rat thyroid epithelia, of ENaC and Nedd4-2 cDNAs leads to a significant reduction in amiloride-sensitive currents, confirming a role in Na+ transport regulation. In vitro binding studies demonstrated that individual PY motifs of alpha-, beta-, and gamma-ENaC have strong affinity for WW domains 3 and 4 but not 1 and 2. These studies indicate that alternate transcripts of Nedd4-2 may interact with ENaC differently. Understanding the function of variant proteins will increase our knowledge of the role of hNedd4-2 in the regulation of ENaC and define protein domains important for Nedd4-2 function.
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PMID:Alternate promoters and variable splicing lead to hNedd4-2 isoforms with a C2 domain and varying number of WW domains. 1287 68

The epithelial Na(+) channel (ENaC) regulates epithelial salt and water reabsorption, processes that require significant expenditure of cellular energy. To test whether the ubiquitous metabolic sensor AMP-activated kinase (AMPK) regulates ENaC, we examined the effects of AMPK activation on amiloride-sensitive currents in Xenopus oocytes and polarized mouse collecting duct mpkCCD(c14) cells. Microinjection of oocytes expressing mouse ENaC (mENaC) with either active AMPK protein or an AMPK activator inhibited mENaC currents relative to controls as measured by two-electrode voltage-clamp studies. Similarly, pharmacological AMPK activation or overexpression of an activating AMPK mutant in mpkCCD(c14) cells inhibited amiloride-sensitive short circuit currents. Expression of a degenerin mutant beta-mENaC subunit (S518K) along with wild type alpha and gamma increased the channel open probability (P(o)) to approximately 1. However, AMPK activation inhibited currents similarly with expression of either degenerin mutant or wild type mENaC. Single channel recordings under these conditions demonstrated that neither P(o) nor channel conductance was affected by AMPK activation. Moreover, expression of a Liddle's syndrome-type beta-mENaC mutant (Y618A) greatly enhanced ENaC whole cell currents relative to wild type ENaC controls and prevented AMPK-dependent inhibition. These findings indicate that AMPK-dependent ENaC inhibition is mediated through a decrease in the number of active channels at the plasma membrane (N), presumably through enhanced Nedd4-2-dependent ENaC endocytosis. The AMPK-ENaC interaction appears to be indirect; AMPK did not bind ENaC in cells, as assessed by in vivo pull-down assays, nor did it phosphorylate ENaC in vitro. In summary, these results suggest a novel mechanism for coupling ENaC activity and renal Na(+) handling to cellular metabolic status through AMPK, which may help prevent cellular Na(+) loading under hypoxic or ischemic conditions.
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PMID:Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. 1575 79

Mutations that disrupt a PY motif in epithelial Na(+) channel (ENaC) subunits increase surface expression of Na(+) channels in the collecting duct, resulting in greater Na(+) reabsorption. Nedd4 and Nedd4-2 have been identified as ubiquitin ligases that can interact with ENaC via its PY motifs to regulate channel activity. We recently reported that human Nedd4-2 (hNedd4-2) is expressed as many isoforms because of alternative promoter usage and/or variable splicing. To understand the relevance of hNedd4-2 isoforms for collecting duct Na(+) transport, we studied the interaction with ENaC and the intracellular localization and function of the following three naturally occurring hNedd4-2 isoforms: full-length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the NH(2)-terminal C2 domain (Nedd4-2DeltaC2), and Nedd4-2 lacking the C2 domain and WW domains 2 and 3 (Nedd4-2DeltaWW2,3). Nedd4-2 and Nedd4-2DeltaC2 associate with ENaC and robustly reduce Na(+) transport in Xenopus oocytes, whereas the interaction with and functional effect of Nedd4-2DeltaWW2,3 on ENaC is weak. Nedd4-2 is expressed in the mouse collecting duct, and overexpression of Nedd4-2 reduces endogenous ENaC activity in a collecting duct cell line. This reduction in ENaC activity can be reversed early with exposure to dexamethasone, an effect that is associated with an increase in sgk1 abundance. The C2 domain is required to target Nedd4-2 to the plasma membrane in response to elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) in MDCK cells, although it does not appear to mediate the inhibitory effect of [Ca(2+)](i) on Na(+) transport. Our data illustrate that naturally occurring hNedd4-2 isoforms differentially associate with ENaC to regulate its activity.
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PMID:Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. 1581 30

Aldosterone plays a central role in Na+ homeostasis by controlling Na+ reabsorption in the aldosterone-sensitive distal nephron involving the epithelial Na+ channel (ENaC). Part of the effects of aldosterone is mediated by serum and glucocorticoid-induced kinase 1 (Sgk1), a Ser/Thr kinase whose expression is rapidly induced by aldosterone and that increases in heterologous expression systems ENaC cell surface abundance and activity. Previous work in Xenopus laevis oocytes suggested that Sgk1 phosphorylates specific residues (Ser212 and Ser328) on the ubiquitin-protein ligase Nedd4-2, an enzyme that directly interacts with ENaC and negatively controls channel density at the plasma membrane. It further indicated that phosphorylation of Nedd4-2 led to impairment of ENaC/Nedd4-2 interaction and consequently to more channels at the cell surface. These data suggested a novel mode of aldosterone-dependent action, yet this was not demonstrated formally in epithelial cells that physiologically express ENaC. Here it is shown, with the use of an anti-phospho-Ser328-mNedd4-2 antibody, that 2 to 6 h of aldosterone treatment induces an increase in Nedd4-2 phosphorylation, both in a mouse cortical collecting duct cell line (mpkCCDcl4) and in kidneys of adrenalectomized rats. This augmentation, which is accompanied by a raise in Sgk1 expression and transepithelial Na+ transport, is sensitive to phosphatidylinositol-3 kinase inhibition, as is Sgk1 phosphorylation and Na+ transport. Hence, these data provide evidence in cortical collecting duct cells in vitro and in vivo that Sgk1-dependent phosphorylation of Nedd4-2 is part of the aldosterone response.
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PMID:Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression is accompanied by Nedd4-2 phosphorylation and increased Na+ transport in cortical collecting duct cells. 1595 25

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 alpha, beta, and gammaENaC (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.
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PMID:Minireview: regulation of epithelial Na+ channel trafficking. 1615 Aug 99

Chronic metabolic acidosis (CMA) is associated with decreased NaCl reabsorption in the proximal tubule (PT). However, the effect of CMA on Na(+) transport in the distal tubule (DT) and collecting duct (CD) is poorly understood. Rats were placed in metabolic cages and had access to water (control), 0.28 M NH(4)Cl, or 0.28 M KCl solutions in a pair-feeding protocol for 5 days (5d). Metabolic acidosis developed within 24 h in NH(4)Cl-, but not in KCl-loaded rats. Interestingly, NH(4)Cl- but not KCl-loaded rats exhibited a significant natriuresis after 24 h of treatment. Urinary Na(+) excretion increased from 1.94 to 2.97 meq/24 h (P < 0.001) and returned to below baseline level (1.67 meq/l) after 5d of CMA. The protein abundance of the cortical Na-Cl cotransporter (NCC) remained unchanged at 24 h, but increased significantly (P < 0.01) after 5d of CMA. The protein abundance of alpha-, beta-, and gamma-subunits of the epithelial Na(+) channel (ENaC) in the cortex decreased sharply during the first 24 h and then returned to baseline levels after 5d of CMA. Interestingly, Sgk1 expression decreased after 24 h (-31%, P < 0.05) and then returned to baseline after 5d of CMA. Nedd4-2 expression was not altered during CMA. CMA enhanced serum aldosterone levels by 54% and increased the expression of aldosterone synthase in the adrenal gland by 134% after 5d of CMA. In conclusion, metabolic acidosis has dual effects on urinary Na(+) excretion. The early natriuresis results from decreased Na(+) reabsorption in the PT and Sgk1-related decreased ENaC activity in the DT and CD. Aldosterone-induced upregulation of NCC, Sgk1, and ENaC likely contributes to the antinatriuretic phase of metabolic acidosis. This adaptation prevents Na(+) wasting and volume depletion during chronic acid insult.
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PMID:Metabolic acidosis has dual effects on sodium handling by rat kidney. 1649 12


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