scholarly journals Hypoxia and β2-Agonists Regulate Cell Surface Expression of the Epithelial Sodium Channel in Native Alveolar Epithelial Cells

2002 ◽  
Vol 277 (49) ◽  
pp. 47318-47324 ◽  
Author(s):  
Carole Planès ◽  
Marcel Blot-Chabaud ◽  
Michael A. Matthay ◽  
Sylviane Couette ◽  
Tokujiro Uchida ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Surface Expression ◽  
Alveolar Epithelial Cells ◽  
Cell Surface Expression ◽  
Alveolar Epithelial ◽  
Β2 Agonists

COMMD1 downregulates the epithelial sodium channel through Nedd4–2

2010 ◽  
Vol 298 (6) ◽  
pp. F1445-F1456 ◽  
Author(s):  
Ying Ke ◽  
A. Grant Butt ◽  
Marianne Swart ◽  
Yong Feng Liu ◽  
Fiona J. McDonald
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Sodium Channel ◽  
Rat Kidney ◽  
Copper Metabolism ◽  
Epithelial Sodium Channel ◽  
Surface Expression ◽  
Dominant Negative ◽  
Cell Surface Expression ◽  
Xenopus Laevis Oocytes

The epithelial sodium channel (ENaC) is important for the long-term control of Na+ homeostasis and blood pressure. Our previous studies demonstrated that Copper Metabolism Murr1 Domain-containing protein 1 (COMMD1; previously known as Murr1), a protein involved in copper metabolism, inhibited amiloride-sensitive current in Xenopus laevis oocytes expressing ENaC ( J Biol Chem 279: 5429, 2004). In this study, we report that COMMD1 inhibits amiloride-sensitive current in mammalian epithelial cells expressing ENaC, that the COMM domain of COMMD1 is sufficient for this effect, and that knockdown of COMMD1 increases amiloride-sensitive current. COMMD1 is coexpressed with ENaC in rat kidney medulla cells. COMMD1 increased ubiquitin modification of ENaC and decreased its cell surface expression. COMMD1 abolished insulin-stimulated amiloride-sensitive current and attenuated the stimulation of current by activated serum and glucocorticoid-regulated kinase (SGK1). COMMD1 was found to interact with both SGK1 and Akt1/protein kinase B, and knockdown of COMMD1 enhanced the stimulatory effect of both SGK1 and Akt1 on amiloride-sensitive current. COMMD1's effects were reduced in the presence of ENaC proteins containing PY motif mutations, abolished in the presence of a dominant negative form of Nedd4–2, and knockdown of COMMD1 reduced the inhibitory effect of Nedd4–2 on ENaC, but did not enhance current when Nedd4–2 was knocked down. These data suggest that COMMD1 modulates Na+ transport in epithelial cells through regulation of ENaC cell surface expression and this effect is likely mediated via Nedd4–2.

Functional interaction of COMMD3 and COMMD9 with the epithelial sodium channel

2013 ◽  
Vol 305 (1) ◽  
pp. F80-F89 ◽  
Author(s):  
Yong Feng Liu ◽  
Marianne Swart ◽  
Ying Ke ◽  
Kevin Ly ◽  
Fiona J. McDonald
Keyword(s):  
Cell Surface ◽  
Sodium Channel ◽  
Collecting Duct ◽  
Extracellular Fluid ◽  
Copper Metabolism ◽  
Epithelial Sodium Channel ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Endogenous Regulators ◽  
Collecting Duct Cells

The epithelial sodium channel (ENaC) plays an important role in controlling Na+ homeostasis, extracellular fluid volume, and blood pressure. Copper metabolism Murr1 domain-containing protein 1 (COMMD1) interacts with ENaC and downregulates ENaC. COMMD1 belongs to the COMMD family consisting of COMMD1–10, and all COMMD family members share a C-terminal COMM domain. Here, we report that COMMD2–10 also interacts with ENaC, and COMMD3 and COMMD9 were selected for further study. Amiloride-sensitive current in mammalian epithelia expressing ENaC was significantly reduced by COMMD3 or COMMD9, and ENaC expression at the cell surface was significantly decreased in the presence of COMMD3 or COMMD9. COMMD3 and COMMD9 retained their ability to reduce current when COMMD1 was knocked down. COMMD3 and COMMD9 were widely expressed in kidney and were colocalized with ENaC in renal collecting duct cells. These data suggest that COMMD3 and COMMD9 may be endogenous regulators of ENaC to regulate Na+ transport through altering ENaC cell surface expression.

scholarly journals MicroRNA 16 modulates epithelial sodium channel in human alveolar epithelial cells

2012 ◽  
Vol 426 (2) ◽  
pp. 203-208 ◽  
Author(s):  
Prasanna Tamarapu Parthasarathy ◽  
Lakshmi Galam ◽  
Bao Huynh ◽  
Asfiya Yunus ◽  
Toaa Abuelenen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Human Alveolar Epithelial Cells

scholarly journals Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel

2008 ◽  
Vol 294 (5) ◽  
pp. F1157-F1165 ◽  
Author(s):  
Nandita S. Raikwar ◽  
Christie P. Thomas
Keyword(s):  
Cell Surface ◽  
Sodium Channel ◽  
Collecting Duct ◽  
Epithelial Sodium Channel ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Membrane Expression ◽  
Ww Domains ◽  
Ubiquitin Proteasome ◽  
And Function

We previously reported the existence of multiple isoforms of human Nedd4-2 ( Am J Physiol Renal Physiol 285: F916–F929, 2003). When overexpressed in M-1 collecting duct epithelia, full-length Nedd4-2 (Nedd4-2), Nedd4-2 lacking the NH2-terminal C2 domain (Nedd4-2ΔC2), and Nedd4-2 lacking WW domains 2 and 3 (Nedd4-2ΔWW2,3) variably reduce benzamil-sensitive Na+ transport. We investigated the effect of each of the Nedd4-2 isoforms on cell surface expression and ubiquitination of ENaC subunits. We find that αENaC when transfected alone or with β and γENaC is expressed at the cell surface and this membrane expression is variably reduced by coexpression with each of the Nedd4-2 isoforms. Nedd4-2 reduces the half-life of ENaC subunits and enhances the ubiquitination of α, β, and γENaC subunits when expressed alone or together suggesting that each subunit is a target for Nedd4-2-mediated ubiquitination. As has been reported recently, we confirm that the surface-expressed pool of ENaC is multi-ubiquitinated. Inhibitors of the proteasome increase ubiquitination of ENaC subunits and stimulate Na+ transport in M-1 cells consistent with a role for the ubiquitin-proteasome pathway in regulating Na+ transport in the collecting duct.

scholarly journals Hsc70 negatively regulates epithelial sodium channel trafficking at multiple sites in epithelial cells

2013 ◽  
Vol 305 (7) ◽  
pp. C776-C787 ◽  
Author(s):  
Rebecca A. Chanoux ◽  
Calla B. Shubin ◽  
Amal Robay ◽  
Laurence Suaud ◽  
Ronald C. Rubenstein
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Functional Expression ◽  
Surface Expression ◽  
Published Data ◽  
Apical Surface ◽  
Refractory Hypertension ◽  
Channel Trafficking

The epithelial sodium channel (ENaC) plays an important role in homeostasis of blood pressure and of the airway surface liquid, and excess function of ENaC results in refractory hypertension (in Liddle's syndrome) and impaired mucociliary clearance (in cystic fibrosis). The regulation of ENaC by molecular chaperones, such as the 70-kDa heat shock protein Hsc70, is not completely understood. Our previously published data suggest that Hsc70 negatively affects ENaC activity and surface expression in Xenopus oocytes; here we investigate the mechanism by which Hsc70 acts on ENaC in epithelial cells. In Madin-Darby canine kidney cells stably expressing epitope-tagged αβγ-ENaC and with tetracycline-inducible overexpression of Hsc70, treatment with 5 μg/ml doxycycline increased total Hsc70 expression 20%. This increase in Hsc70 expression led to a decrease in ENaC activity and surface expression that corresponded to an increased rate of functional ENaC retrieval from the cell surface. In addition, Hsc70 overexpression decreased the association of newly synthesized ENaC subunits. These data support the hypothesis that Hsc70 inhibits ENaC functional expression at the apical surface of epithelia by regulating ENaC biogenesis and ENaC trafficking at the cell surface.

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