Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.
FASEB J
; 28(2): 791-801, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24200884
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 â¼ 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cloretos
/
Regulador de Condutância Transmembrana em Fibrose Cística
/
Epitélio
/
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article