CFTR directly mediates nucleotide-regulated glutathione flux

Kogan, Ilana; Ramjeesingh, Mohabir; Li, Canhui; Kidd, Jackie F.; Wang, Yanchun; Leslie, Elaine M.; Cole, Susan P.C.; Bear, Christine E.

doi:10.1093/emboj/cdg194

Cited by 197 publications

(137 citation statements)

References 63 publications

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“…In addition to its Cl − channel function, CFTR has been proposed to conduct GSH (8,1,45) and also to downregulate adjacent ENaC activity (11, 46,12,) such that in CF upregulated Na + transport (47,48,49) leads to increased O 2 consumption (14) and cellular hypoxia (10). Hypoxia like that observed for CF airway epithelial cell cultures is known to increase mitochondrial production of ROS (50,15,16,51), and recent measurements of mitochondrial GSH and DNA oxidation have given indications that CF mitochondria are oxidized compared to nonCF (17).…”

Section: Discussionmentioning

confidence: 99%

Organelle redox of CF and CFTR-corrected airway epithelia

Schwarzer¹,

Illek²,

Suh³

et al. 2007

Free Radical Biology and Medicine

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In cystic fibrosis reduced CFTR function may alter redox properties of airway epithelial cells. Redox-sensitive GFP (roGFP1) and imaging microscopy were used to measure redox potentials of cytosol, ER, mitochondria and cell surface of cystic fibrosis nasal epithelial cells and CFTRcorrected cells. We also measured glutathione and cysteine thiol redox states in cell lysates and apical fluids to provide coverage over a range of redox potentials and environments that might be affected by CFTR. As measured with roGFP1, redox potentials at the cell surface (~ -207 ±8 mV) and in the ER (~ -217 ±1 mV) and rates of regulation of the apical fluid and ER lumen following DTT treatment were similar for CF and CFTR-corrected cells. CF and CFTR-corrected cells had similar redox potentials in mitochondria (-344 ±9 mV) and cytosol (-322 ±7 mV). Oxidation of carboxy-dichlorodihydrofluoresceindiacetate and of apical Amplex Red occurred at equal rates in CF and CFTR-corrected cells. Glutathione and cysteine redox couples in cell lysates and apical fluid were equal in CF and CFTR-corrected cells. These quantitative estimates of organelle redox potentials combined with apical and cell measurements using small molecule couples confirmed there were no differences in redox properties of CF and CFTR-corrected cells.

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Section: Discussionmentioning

confidence: 99%

Organelle redox of CF and CFTR-corrected airway epithelia

Schwarzer¹,

Illek²,

Suh³

et al. 2007

Free Radical Biology and Medicine

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show abstract

“…The reason for this seems to be related to the direct or indirect effects of CFTR on GSH transport out of epithelial cells. CFTR may be an important regulator of GSH release into the ELF (29), with deficiency in CFTR associated with lower levels of GSH (26,27) and restoration of chloride channel function leading to increased GSH secretion (28).…”

Section: Discussionmentioning

confidence: 99%

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

McKone

Shao

Frangolias

et al. 2006

Am J Respir Crit Care Med

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Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury. Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease. Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype. Measurements and Main Results

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“…A number of lung diseases are associated with low ELF GSH, such as idiopathic pulmonary fibrosis [54] and the acute respiratory distress syndrome [55], suggesting that chronic inflammation could be partly responsible [56]. Surprisingly, high levels of GSH have been observed in CF sputum, possibly reflecting the large number of airway inflammatory cells present [54,57]. These contrasting observations suggest that ELF and sputum represent different compartments.…”

Section: Antioxidants In the Airway Lumen Mucinmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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Although great strides are being made in the care of individuals with cystic fibrosis (CF), this condition remains the most common fatal hereditary disease in North America. Numerous links exist between progression of CF lung disease and oxidative stress. The defect in CF is the loss of function of the transmembrane conductance regulator (CFTR) protein; recent evidence that CFTR expression and function are modulated by oxidative stress suggests that the loss may result in a poor adaptive response to oxidants. Pancreatic insufficiency in CF also increases susceptibility to deficiencies in lipophilic antioxidants. Finally the airway infection and inflammatory processes in the CF lung are potential sources of oxidants that can affect normal airway physiology and contribute to the mechanisms causing characteristic changes associated with bronchiectasis and loss of lung function. These multiple abnormalities in the oxidant/antioxidant balance raise several possibilities for therapeutic interventions that must be carefully assessed. IntroductionCystic fibrosis (CF) is the most common fatal disease caused by a single gene defect in Europe and North America [1,2]. The defective gene was identified in 1989 [3][4][5] and shown to encode the cystic fibrosis trans-membrane conductance regulator protein (CFTR). CFTR is a cyclic AMP-regulated anion channel with greatest selectivity for chloride, and bicarbonate [6][7][8]. Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands ☆ A list of participants may be found in the Acknowledgments.

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CFTR directly mediates nucleotide-regulated glutathione flux

Cited by 197 publications

References 63 publications

Organelle redox of CF and CFTR-corrected airway epithelia

Organelle redox of CF and CFTR-corrected airway epithelia

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

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