Defective Regulation of Epithelial Cl- Permeability and Protein Secretion in Cystic Fibrosis: The Putative Basic Defect

Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed at low levels in nonepithelial cells. Recently, we demonstrated that CFTR is responsible for cell cycle-dependent adenosine 3',5'-cyclic monophosphate-responsive Cl- permeability in lymphocytes. Agonist responsiveness of cystic fibrosis (CF) lymphocytes was restored by transfection with plasmid containing wild type CFTR cDNA. CFTR mRNA is expressed in the B lymphoid cell line GM03299; however, quantitative reverse transcriptase-polymerase chain reaction indicates that the level of CFTR mRNA is at least 1,000 times lower than in T84 cells. CFTR protein could not be detected by Western blot or by immunoprecipitation of in vitro phosphorylated protein. However, antisense oligonucleotides representing codons 1-12 of CFTR caused a complete inhibition of cell cycle-dependent Cl-permeability [as determined by 6-methoxy-N-(3-sulfopropyl)-quinolinium fluorescence digital-imaging microscopy], thereby inducing normal cells to acquire a "CF phenotype." These studies provide direct evidence that a CFTR-associated Cl- permeability is present and measurable in lymphocytes, even though CFTR mRNA and protein are expressed at low levels.

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Cystic fibrosis treatment: targeting the basic defect

Expert Opinion on Orphan Drugs ◽

10.1080/21678707.2017.1280390 ◽

2017 ◽

Vol 5 (2) ◽

pp. 181-192 ◽

Cited By ~ 2

Author(s):

Pedro Mondejar-Lopez ◽

Maria Dolores Pastor-Vivero ◽

Manuel Sanchez-Solis ◽

Amparo Escribano

Keyword(s):

Cystic Fibrosis ◽

Basic Defect ◽

Treatment Targeting

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Cystic Fibrosis: Towards The Basic Defect

QJM ◽

10.1093/oxfordjournals.qjmed.a068260 ◽

1988 ◽

Keyword(s):

Cystic Fibrosis ◽

Basic Defect

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Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands

Journal of Biological Chemistry ◽

10.1074/jbc.m512766200 ◽

2006 ◽

Vol 281 (11) ◽

pp. 7392-7398 ◽

Cited By ~ 82

Author(s):

Nam Soo Joo ◽

Toshiya Irokawa ◽

Robert C. Robbins ◽

Jeffrey J. Wine

Keyword(s):

Cystic Fibrosis ◽

Basic Defect ◽

Cystic Fibrosis Airway

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Cystic Fibrosis: New Insights into Therapeutic Approaches

Current Respiratory Medicine Reviews ◽

10.2174/1573398x15666190702151613 ◽

2020 ◽

Vol 15 (3) ◽

pp. 174-186

Author(s):

Antonella Tosco ◽

Valeria R. Villella ◽

Valeria Raia ◽

Guido Kroemer ◽

Luigi Maiuri

Keyword(s):

Cystic Fibrosis ◽

Gene Editing ◽

New Technologies ◽

Therapeutic Approaches ◽

Basic Defect ◽

Recent Advances ◽

The Future ◽

Cftr Protein

Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over the last few years, new technologies have been developed, and gene editing strategies are now moving toward a one-time cure. This review will summarize recent advances in etiological therapies that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve its function. Moreover, we will discuss how proteostasis regulators can modify the environment in which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.

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The basic defect in cystic fibrosis

Science ◽

10.1126/science.2544028 ◽

1989 ◽

Vol 244 (4911) ◽

pp. 1423-1423 ◽

Cited By ~ 7

Author(s):

I. Levitan

Keyword(s):

Cystic Fibrosis ◽

Basic Defect

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Cystic fibrosis

10.1093/med/9780199568741.003.0132 ◽

2018 ◽

Author(s):

Rowland J. Bright-Thomas ◽

Andrew M. Jones

Keyword(s):

Cystic Fibrosis ◽

Gastrointestinal Tract ◽

Reproductive System ◽

Autosomal Recessive ◽

Pulmonary Infection ◽

Autosomal Recessive Disorder ◽

Carrier State ◽

Male Reproductive System ◽

Morbidity And Mortality ◽

Basic Defect

Cystic fibrosis is the most common lethal autosomal recessive disorder in Caucasians. There is no known survival advantage of the heterozygote carrier state. Chronic progressive pulmonary infection and bronchiectasis are the major causes of morbidity and mortality. The disease affects all ductal systems where the basic defect is manifest, including the pancreas, gastrointestinal tract, sinuses, hepatobiliary system, and male reproductive system, and has significant effects on nutrition and growth.

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Localization of Cl- conductance in normal and Cl- impermeability in cystic fibrosis sweat duct epithelium

AJP Cell Physiology ◽

10.1152/ajpcell.1989.257.4.c727 ◽

1989 ◽

Vol 257 (4) ◽

pp. C727-C735 ◽

Cited By ~ 20

Author(s):

M. M. Reddy ◽

P. M. Quinton

Keyword(s):

Cystic Fibrosis ◽

Basolateral Membrane ◽

Voltage Divider ◽

Sweat Duct ◽

Basolateral Membranes ◽

Duct Epithelium ◽

Voltage Divider Ratio ◽

Normal Duct ◽

Cl Conductance ◽

Cl Permeability

We studied the Cl- permeability properties of apical and basolateral membranes of human reabsorptive sweat duct (RSD) from normal and cystic fibrosis (CF) subjects. In normal ducts, Cl- substitution by impermeant anion gluconate in the lumen increased the voltage divider ratio (VDR) from 4.8 +/- 0.9 to 7.0 +/- 1.1 (n = 8, P less than 0.05), whereas Cl- substitution in the contraluminal bath decreased the VDR from 3.2 +/- 0.7 to 1.9 +/- 0.4 (n = 7, P less than 0.05). These results are consistent with a significant Cl- permeability in both apical and basolateral membranes of normal ducts. Amiloride (10(-4) M) in the lumen of normal ducts resulted in a small increase in VDR from 4.2 +/- 0.6 to 5.0 +/- 0.8 (n = 10, P less than 0.05), whereas the current-induced basolateral membrane voltage deflections (delta Vb) increased from 6.9 +/- 1.3 to 7.7 +/- 1.2 mV, suggesting that inhibition of Na+ permeability decreased basolateral membrane Cl- permeability. In the absence of luminal Cl-, amiloride decreased delta Vb and induced much greater effect on VDR (from 5.2 +/- 1.1 to 10.8 +/- 2.3, n = 9, P less than 0.05) than in the presence of Cl-. Likewise, in the presence of amiloride, Cl- substitution in the lumen had greater effect on VDR (increased from 3.5 +/- 0.5 0.5 to 10.0 +/- 1.5, n = 15, P less than 0.05) than in the absence of amiloride. These results indicate that Na+ conductance in the apical membrane of the normal duct is significantly smaller than Cl- conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

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