Chronic β2AR stimulation limits CFTR activation in human airway epithelia

JCI Insight
John J BrewingtonJ P Clancy

Abstract

Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to a...Continue Reading

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Citations

Apr 3, 2020·Journal of Cellular Physiology·Rui-Gang ZhangWing-Hung Ko
Mar 12, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Kristin M HudockJohn Paul Clancy
Apr 6, 2021·Frontiers in Immunology·Dan J K YomboSatish K Madala
Jan 13, 2022·American Journal of Physiology. Lung Cellular and Molecular Physiology·Ciaran A ShaughnessyPamela L Zeitlin

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Methods Mentioned

BETA
RNAseq
Protein Assay
ELISA
RNA-seq

Software Mentioned

R package DESeq2
Nikon Elements software
Imaris Bitplane
Kallisto
Imaris
Graphpad Prism
ImageJ
Nikon Elements
Acquire and Analyze

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