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Anchored PDE4 regulates chloride conductance in wild‐type and ΔF508‐CFTR human airway epithelia
Author(s) -
Blanchard Elise,
Zlock Lorna,
Lao Anna,
Mika Delphine,
Namkung Wan,
Xie Moses,
Scheitrum Colleen,
Gruenert Dieter C.,
Verkman Alan S.,
Finkbeiner Walter E.,
Conti Marco,
Richter Wito
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-240861
Subject(s) - potentiator , cystic fibrosis transmembrane conductance regulator , cystic fibrosis , chloride channel , chemistry , δf508 , endocrinology , mutation , mutant , medicine , wild type , microbiology and biotechnology , biology , biochemistry , pharmacology , gene
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA‐dependent activation of CFTR in primary human bronchial epithelial cells. In non‐CF cells, PDE4 inhibition increased CFTR activity under basal conditions (Δ I SC 7.1 μA/cm 2 ) and after isoproterenol stimulation (increased Δ I SC from 13.9 to 21.0 μA/cm 2 ) and slowed the return of stimulated CFTR activity to basal levels by > 3‐fold. In cells homozygous for Δ F508‐CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ~25% of the chloride conductance observed in non‐CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.—Blanchard, E., Zlock, L., Lao, A., Mika, D., Namkung, W., Xie, M., Scheitrum, C., Gruenert, D.C., Verkman, A.S., Finkbeiner, W.E., Conti, M., Richter, W. Anchored PDE4 regulates chloride conductance in wild type and ΔF508‐CFTR human airway epithelia. FASEB J. 28, 791–801 (2014). www.fasebj.org