The Cystic Fibrosis Transmembrane Conductance Regulator Impedes Proteolytic Stimulation of the Epithelial Na+ Channel

Gentzsch, Martina; Dang, Hong; Dang, Yan L.; Garcı́a-Caballero, Agustı́n; Suchindran, Hamsa; Boucher, Richard C.; Stutts, M. Jackson

doi:10.1074/jbc.m110.155259

Cited by 93 publications

(85 citation statements)

References 46 publications

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“…Besides its previously described roles in the modulation of airway inflammation, mucus hypersecretion, bacterial killing, and proteolytic lung and immune cell damage [32,[39][40][41][42], NE can activate ENaC by proteolytic cleavage and removal of ''inhibitory'' segments, probably leading to a conformational change of the channel that improves its conductivity for Na + [43,44]. Interestingly, a recent study showed that wild-type CFTR, but not DF508, interacts with ENaC in the plasma membrane of airway epithelial cells and, thus, may impede the proteolytic stimulation of ENaC by NE and potentially other extracellular proteases released by inflammatory cells [45,46]. These results suggest that lack of this ''anti-proteolytic'' function of CFTR may contribute to increased Na + absorption in chronically inflamed CF airways, and may explain why ENaC-mediated Na + transport was not elevated in newborn CF pigs prior to the onset of chronic neutrophilic airway inflammation [36].…”

Section: Airway Proteases Aggravate Basic Cf Ion Transport Defectmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation DF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging. @ERSpublications CFTR dysfunction causes CF and may be implicated in more common chronic obstructive lung diseases, such as COPD

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Section: Airway Proteases Aggravate Basic Cf Ion Transport Defectmentioning

confidence: 99%

CFTR: cystic fibrosis and beyond

2014

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“…The mechanism underlying this functional interaction is, however, controversial, having been variously attributed to changes in intracellular chloride affecting ENaC activity (25, 54, 230), through changes in electrical driving force (73,181,202), to technical issues surrounding efficiency of voltage clamping (282). CFTR and ENaC may directly interact, based on evidence obtained from planar lipid bilayer and fluorescence resonance energy transfer (FRET) studies (37, 39), and from studies demonstrating that wild-type, but not ⌬F508-CFTR, protects ENaC from proteolytic cleavage, thereby limiting the number of channels in the highly active cleaved ENaC pool (147). Wild-type CFTR may also restrict the activity of ENaC by limiting ENaC expression and trafficking to the surface, an effect that was not observed in cells overexpressing ⌬F508-CFTR (331).…”

Section: Conditions Associated With Enac Hyperactivity: Hypertensionmentioning

confidence: 99%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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“…Recently, Gentzsch et al (20) showed that CFTR coimmunoprecipitates with ENaC and inhibits its activity by decreasing proteolysis of its extracellular domains. However, these studies were conducted either in Xenopus oocytes with heterologous expression of ENaC and CFTR or in cultured human bronchial cells expressing native ENaC and CFTR.…”

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confidence: 99%

“…It functions as a cAMP-regulated Cl Ϫ channel (2) and controls other ion conductive pathways including epithelial Cl Ϫ and Na ϩ channels (53,58). Putative mechanisms responsible for the negative regulation of ENaC by CFTR (34) include physical interaction between these two proteins, higher levels of intracellular Cl Ϫ , and CFTR inhibition of ENaC subunits cleavage by proteases (6,7,20,36).…”

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confidence: 99%