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Phosphodiesterase 8A Regulates CFTR Activity in Airway Epithelial Cells.
Turner, Mark J; Sato, Yukiko; Thomas, David Y; Abbott-Banner, Kathy; Hanrahan, John W.
Afiliación
  • Turner MJ; Department of Physiology, McGill University, Montréal, QC, Canada, mark.turner2@mcgill.ca.
  • Sato Y; Cystic Fibrosis Translational Research Centre, McGill University, Montréal, QC, Canada.
  • Thomas DY; Department of Physiology, McGill University, Montréal, QC, Canada.
  • Abbott-Banner K; Cystic Fibrosis Translational Research Centre, McGill University, Montréal, QC, Canada.
  • Hanrahan JW; Cystic Fibrosis Translational Research Centre, McGill University, Montréal, QC, Canada.
Cell Physiol Biochem ; 55(6): 784-804, 2021 Dec 23.
Article en En | MEDLINE | ID: mdl-34936285
BACKGROUND/AIMS: Cystic fibrosis transmembrane conductance regulator (CFTR), the anion channel that is defective in cystic fibrosis (CF), is phosphorylated and activated by cAMP-dependent protein kinase (PKA). cAMP levels are downregulated by a large family of phosphodiesterases that have variable expression in different cell types. We have previously observed high levels of PDE8A expression in well-differentiated primary human bronchial epithelial (pHBE) cells and thus aimed to assess whether it played a role in cAMP-dependent regulation of CFTR activity. METHODS: We assessed the effect of the selective PDE8 inhibitor PF-04957325 (PF) on intracellular cAMP levels ([cAMP]i) in well differentiated pHBE cells from non-CF or CF donors and also in CFBE41o- cells that stably express wild-type CFTR (CFBE41o- WT) using ELISA and FRET-FLIM microscopy. CFTR channel function was also measured using electrophysiological recordings from pHBE and CFBE41o- WT cells mounted in Ussing Chambers. RESULTS: PDE8 inhibition elevated [cAMP]i in well-differentiated pHBE cells and stimulated wild-type CFTR-dependent ion transport under basal conditions or after cells had been pre-stimulated with physiological cAMP-elevating agents. The response to PDE8 inhibition was larger than to PDE3 or PDE5 inhibition but smaller and synergistic with that elicited by PDE4 inhibition. CRISPR Cas9-mediated knockdown of PDE8A enhanced CFTR gene and protein expression yet reduced the effect of PDE8 inhibition. Acute pharmacological inhibition PDE8 increased CFTR activity in CF pHBE cells (F508del/F508del and F508del/R117H-5T) treated with clinically-approved CFTR modulators. CONCLUSION: These results provide the first evidence that PDE8A regulates CFTR and identifies PDE8A as a potential target for adjunct therapies to treat CF.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: 3',5'-AMP Cíclico Fosfodiesterasas / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Mucosa Respiratoria / Fibrosis Quística / Células Epiteliales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Physiol Biochem Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2021 Tipo del documento: Article Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: 3',5'-AMP Cíclico Fosfodiesterasas / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Mucosa Respiratoria / Fibrosis Quística / Células Epiteliales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Physiol Biochem Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2021 Tipo del documento: Article Pais de publicación: Alemania