scholarly journals Counteracting suppression of CFTR and voltage-gated K+ channels by a bacterial pathogenic factor with the natural product tannic acid

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yajamana Ramu ◽  
Yanping Xu ◽  
Hyeon-Gyu Shin ◽  
Zhe Lu
Keyword(s):  
Lung Disease ◽  
Natural Product ◽  
Tannic Acid ◽  
Host Immunity ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Chemical Library ◽  
K Channels ◽  
Voltage Gated ◽  
Cystic Fibrosis Transmembrane

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause recurring bacterial infection in CF patients' lungs. However, the severity of CF lung disease correlates poorly with genotype. Antibiotic treatment helps dramatically prolong patients' life. The lung disease generally determines prognosis and causes most morbidity and mortality; early control of infections is thus critical. Staphylococcus aureus is a main cause of early infection in CF lungs. It secretes sphingomyelinase (SMase) C that can suppress CFTR activity. SMase C also inhibits voltage-gated K+ channels in lymphocytes; inhibition of these channels causes immunosuppression. SMase C's pathogenicity is further illustrated by the demonstration that once Bacillus anthracis is engineered to express high levels of SMase C, the resulting mutant can evade the host immunity elicited by a live vaccine because additional pathogenic mechanisms are created. By screening a chemical library, we find that the natural product tannic acid is an SMase C antidote.

scholarly journals Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents.

1992 ◽  
Vol 100 (4) ◽  
pp. 573-591 ◽  
Author(s):  
D N Sheppard ◽  
M J Welsh
Keyword(s):  
Cystic Fibrosis ◽  
Voltage Dependence ◽  
K Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
K Channels ◽  
Intracellular Atp ◽  
Cl Channel ◽  
Cl Channels ◽  
Cystic Fibrosis Transmembrane

The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that is regulated by cAMP-dependent phosphorylation and by intracellular ATP. Intracellular ATP also regulates a class of K+ channels that have a distinct pharmacology: they are inhibited by sulfonylureas and activated by a novel class of drugs called K+ channel openers. In search of modulators of CFTR Cl- channels, we examined the effect of sulfonylureas and K+ channel openers on CFTR Cl- currents in cells expressing recombinant CFTR. The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. Inhibition by both agents showed little voltage dependence and developed slowly; > 90% inhibition occurred 3 min after adding 1 mM tolbutamide or 100 microM glibenclamide. The effect of tolbutamide was reversible, while that of glibenclamide was not. In contrast to their activating effect on K+ channels, the K+ channel openers, diazoxide, BRL 38227, and minoxidil sulfate inhibited CFTR Cl- currents. Half-maximal inhibition was observed at approximately 250 microM diazoxide, 50 microM BRL 38227, and 40 microM minoxidil sulfate. The rank order of potency for inhibition of CFTR Cl- currents was: glibenclamide < BRL 38227 approximately equal to minoxidil sulfate > tolbutamide > diazoxide. Site-directed mutations of CFTR in the first membrane-spanning domain and second nucleotide-binding domain did not affect glibenclamide inhibition of CFTR Cl- currents. However, when part of the R domain was deleted, glibenclamide inhibition showed significant voltage dependence. These agents, especially glibenclamide, which was the most potent, may be of value in identifying CFTR Cl- channels. They or related analogues might also prove to be of value in treating diseases such as diarrhea, which may involve increased activity of the CFTR Cl- channel.

scholarly journals The CFTR and ENaC debate: how important is ENaC in CF lung disease?

2012 ◽  
Vol 302 (11) ◽  
pp. L1141-L1146 ◽  
Author(s):  
James F. Collawn ◽  
Ahmed Lazrak ◽  
Zsuzsa Bebok ◽  
Sadis Matalon
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ongoing Debate ◽  
The Subject ◽  
Cystic Fibrosis Transmembrane ◽  
Epithelial Sodium Channel Enac

Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease.

scholarly journals A Pharmacologic Approach to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Smoking Related Lung Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e39809 ◽  
Author(s):  
Peter A. Sloane ◽  
Suresh Shastry ◽  
Andrew Wilhelm ◽  
Clifford Courville ◽  
Li Ping Tang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

scholarly journals Acquired cystic fibrosis transmembrane conductance regulator protein (CFTR) dysfunction and cigarette smoking

2019 ◽  
Vol 7 (30) ◽  
pp. 43-46
Author(s):  
Jonathan Kopel
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Transmembrane Conductance Regulator ◽  
Inherited Disease ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Regulator Protein ◽  
Increase Risk ◽  
Nasal Potential Difference ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) remains a prevalent genetically inherited disease in Caucasianpopulations. Investigation of the respiratory symptoms which occur in patients with CF helps usunderstand the pathophysiology of chronic lung disease. Environmental insults, such as cigarettesmoke, can reduce the cystic fibrosis transmembrane receptor (CFTR) function or expressionleading to an acquired CF phenotype and could contribute to the development and progressionof smoking-related lung disease. However, it is uncertain if the acquired CF phenotype can bediagnosed with the same methods, such as the sweat chloride test and the measurementof nasal potential difference, used for genetically-acquired CF. More studies are needed toinvestigate the prevalence of acquired CFTR dysfunction and the differences between acquiredand genetically-inherited CFTR dysfunction. Overall, acquired CFTR dysfunction challengesthe distinction between genetic and acquired disorders, suggesting that environmental agentsmay modulate the functions of genes and the increase risk for pulmonary disease.

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