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Research Article Free access | 10.1172/JCI118819

Activation of endogenous deltaF508 cystic fibrosis transmembrane conductance regulator by phosphodiesterase inhibition.

T J Kelley, L Al-Nakkash, C U Cotton, and M L Drumm

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.

Find articles by Kelley, T. in: JCI | PubMed | Google Scholar

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.

Find articles by Al-Nakkash, L. in: JCI | PubMed | Google Scholar

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.

Find articles by Cotton, C. in: JCI | PubMed | Google Scholar

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.

Find articles by Drumm, M. in: JCI | PubMed | Google Scholar

Published July 15, 1996 - More info

Published in Volume 98, Issue 2 on July 15, 1996
J Clin Invest. 1996;98(2):513–520. https://doi.org/10.1172/JCI118819.
© 1996 The American Society for Clinical Investigation
Published July 15, 1996 - Version history
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Abstract

Many heterologously expressed mutants of the cystic fibrosis transmembrane conductance regulator (CFTR) exhibit residual chloride channel activity that can be stimulated by agonists of the adenylate cyclase/protein kinase A pathway. Because of clinical implications for cystic fibrosis of activating mutants in vivo, we are investigating whether deltaF508, the most common disease-associated CFTR mutation, can be activated in airway epithelial cells. We have found that, 36Cl- efflux can be stimulated 19-61% above baseline by beta-adrenoreceptor agonists and cGI-phosphodiesterase inhibitors in transformed nasal polyp (CF-T43) cells homozygous for the deltaF508 mutation. The increase in 36Cl- permeability is diminished by protein kinase A inhibitors and is not mediated by an increase in intracellular calcium concentrations. Preincubation of CF-T43 cells with CFTR anti-sense oligonucleotides prevented an increase in 36Cl- efflux in response to beta-agonist and phosphodiesterase inhibitor. Primary cells isolated from CF nasal polyps gave similar results. These data indicate that endogenous levels of deltaF508 protein can be stimulated to increase 36Cl- permeability in airway epithelial cells.

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