Regulatory interactions of N1303K-CFTR and ENaC in <i>Xenopus</i> oocytes: evidence that chloride transport is not necessary for inhibition of ENaC

Suaud, Laurence; Yan, Wusheng; Carattino, Marcelo D.; Robay, Amal; Kleyman, Thomas R.; Rubenstein, Ronald C.

doi:10.1152/ajpcell.00064.2006

Cited by 14 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, isolation of type II pneumocytes from TREK-1 deficient mice will allow us in future experiments to determine whether alterations in epithelial cell activation are contributing to the increased sensitivity to HO in these mice. Another important point to address in future studies is whether the effects of TREK-1 deficiency are related to alterations in cellular K + handling, or whether TREK-1 can exert functions that are unrelated to its role as a K + channel as for example described for CFTR[38, 39]. In a recently published study[40] we showed that TREK-1 regulates the mechanobiological properties of AECs by altering F-actin metabolism and overall cellular stiffness.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Schwingshackl

Teng

Makena

et al. 2014

Critical Care Medicine

View full text Add to dashboard Cite

Objective We previously reported the expression of the 2-pore domain K+ channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury. Design Laboratory animal experiments. Setting University research laboratory. Subjects Wild type and TREK-1 deficient mice. Interventions Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours. Measurements and Main Results Hyperoxia exposure accentuated lung injury in TREK-1 deficient mice but not controls, resulting in increased in Lung Injury Scores (LIS), broncho-alveolar lavage (BAL) fluid cell numbers and cellular apoptosis, and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage, increased LIS and BAL fluid cell numbers in control but not TREK-1 deficient mice. At baseline and after hyperoxia exposure BAL cytokine levels were unchanged in TREK-1 deficient mice compared to controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in BAL IL-6, MCP-1 and TNF-α levels in both mouse types, but the increase in IL-6 and MCP-1 levels was less prominent in TREK-1 deficient mice than in controls. Lung tissue MIP-2, KC and IL-1β gene expression was not altered by hyperoxia in TREK-1 deficient mice compared to controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired TNF-α secretion from TREK-1 deficient macrophages. Conclusion TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxia-induced lung injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Schwingshackl

Teng

Makena

et al. 2014

Critical Care Medicine

View full text Add to dashboard Cite

show abstract

“…Inhibition of ENaC by intracellular Cl − has also been proposed as an indirect mechanism for the regulation of ENaC by CFTR (Konig et al 2001; Bachhuber et al 2005). While this cannot be excluded as a physiological mechanism to regulate ENaC, CFTR mutants that can still conduct Cl − , such as N1303K, also fail to inhibit ENaC (Suaud et al 2007), suggesting that the exact mechanism whereby CFTR regulates ENaC remains unknown.…”

Section: Cftr–enac Interactions and Na+ Hyperabsorptionmentioning

confidence: 99%

Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

Hobbs¹,

Tan²,

Tarran

2013

The Journal of Physiology

View full text Add to dashboard Cite

Key points Lung hydration and mucus clearance rates are set by a balance between CFTR‐mediated Cl− secretion and ENaC‐led Na+ absorption. In CF airways, CFTR is diminished, and ENaC is upregulated, leading to mucus dehydration and increased chance of infection. Evidence for ENaC upregulation in CF airways includes electrophysiological evidence, increased ASL absorption rates, increased cleavage of CF ENaC and increased basolateral Na+/K+ ATPase activity in CF airways. The mechanism of Na+ hyperabsorption in CF airways is unknown and it may be due to altered protein‐protein interactions and/or increased proteolysis of ENaC in CF airways. However, inhibition of ENaC is predicted to increase CF mucus hydration/clearance and thus, ENaC remains an important therapeutic target for the treatment of CF lung disease. Abstract Airway epithelia absorb Na+ through the epithelial Na+ channel (ENaC) and secrete Cl− through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid hydration to permit efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the CFTR gene that lead to the reduction or elimination of the CFTR protein. CF is a multi‐organ disease that affects epithelia lining the intestines, lungs, pancreas, sweat ducts and vas deferens, among others. CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl−/HCO3− and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. Rehydrating CF mucus has become a recent clinical focus and yields important end‐points for clinical trials. However, while ENaC hyperactivity in CF airways has been detected in vivo and in vitro, recent data have brought the role of ENaC in CF lung disease pathogenesis into question. This review will focus on our current understanding of the contribution of ENaC to CF pathogenesis.

show abstract

“…Despite a precedence for this type of regulation of ENaC in mouse salivary duct epithelia [32], this hypothesis remains to be tested in the airways, and other investigators using Xenopus oocytes have reported that ENaC is still regulated appropriately following co-injection of αβγENaC and a non-Cl-conducting CFTR mutant [139]. The interaction between these two ion channels may be variable, and in the sweat glands, where Cl − absorption rather than Cl − secretion occurs under basal conditions, ENaC is activated in parallel with CFTR rather than being inactivated [115].…”

Section: Regulation Of Enac By Intracellular 2nd Messengersmentioning

confidence: 99%

Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases

Gaillard

Kota

Gentzsch

et al. 2010

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Mammalian airways are protected from infection by a thin film of airway surface liquid (ASL) which covers airway epithelial surfaces and acts as a lubricant to keep mucus from adhering to the epithelial surface. Precise regulation of ASL volume is essential for efficient mucus clearance and too great a reduction in ASL volume causes mucus dehydration and mucus stasis which contributes to chronic airway infection. The epithelial Na + channel (ENaC) is the rate-limiting step that governs Na + absorption in the airways. Recent in vitro and in vivo data have demonstrated that ENaC is a critical determinant of ASL volume and hence mucus clearance. ENaC must be cleaved by either intracellular furin-type proteases or extracellular serine proteases to be active and conduct Na + , and this process can be inhibited by protease inhibitors. ENaC can be regulated by multiple pathways, and once proteolytically cleaved ENaC may then be inhibited by intracellular second messengers such as cAMP and PIP 2 . In the airways, however, regulation of ENaC by proteases seems to be the predominant mode of regulation since knockdown of either endogenous serine proteases such as prostasin, or inhibitors of ENaC proteolysis such as SPLUNC1, has large effects on ENaC activity in airway epithelia. In this review, we shall discuss how ENaC is proteolytically cleaved, how this © Springer-Verlag 2010Correspondence to: Robert Tarran, robert_tarran@med.unc.edu. NIH Public Access

show abstract

Regulatory interactions of N1303K-CFTR and ENaC in Xenopus oocytes: evidence that chloride transport is not necessary for inhibition of ENaC

Cited by 14 publications

References 35 publications

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Deficiency of the Two-Pore-Domain Potassium Channel TREK-1 Promotes Hyperoxia-Induced Lung Injury

Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases

Contact Info

Product

Resources

About