title: Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.
abstract: 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 (ΔISC 7.1 μA/cm(2)) and after isoproterenol stimulation (increased ΔISC 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 ΔF508-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.
authors.affiliation: 1Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, 513 Parnassus Ave., Box 0556, San Francisco, CA 94143-0556, USA. richterw@obgyn.ucsf.edu.
authors.forename: Elise
authors.initials: E
authors.lastname: Blanchard
authors.forename: Lorna
authors.initials: L
authors.lastname: Zlock
authors.forename: Anna
authors.initials: A
authors.lastname: Lao
authors.forename: Delphine
authors.initials: D
authors.lastname: Mika
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
authors.forename: Moses
authors.initials: M
authors.lastname: Xie
authors.forename: Colleen
authors.initials: C
authors.lastname: Scheitrum
authors.forename: Dieter C
authors.initials: DC
authors.lastname: Gruenert
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015363:Quinolones / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology
chemical_list: D002712:Chlorides; D015363:Quinolones; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C021294:cilostamide; D000584:Amiloride; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram
keywords: cAMP; corrector; cyclic nucleotide phosphodiesterase; cystic fibrosis