Severe Hypoxia Reduces Adenylyl Cyclase 6 Expression and Function in Bronchial Epithelial Cells

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Abstract
Hypoxia is associated with a range of maladies, inflammation, and impaired immunity. The airway epithelial barrier contends with constant exposure to microbes but can be weakened with hypoxia and diseases, such as cystic fibrosis (CF). People with CF (pwCF) have defective cystic fibrosis transmembrane conductance regulator (CFTR) function leading to reduced immune function, excess mucous accumulation, and chronic infection. CFTR is a cAMP‐dependent anion channel that is regulated in part by adenylyl cyclase 6 (AC6). G protein‐coupled receptors (GPCRs) such as the chemosensory bitter taste receptors (T2Rs) have been shown to alter inhibitory G proteins and cAMP levels. T2Rs also mediate innate immunity responses and detect quorum sensing molecules (QSMs) through T2R14. The impact of hypoxia on these processes, in human airways, has not yet been characterized. We analyzed protein expression and functional endpoints at normal (21%), mild (10%), and severe (1%) oxygen levels to establish the effects of hypoxia on these processes in human bronchial epithelial cells. Our results show that severe hypoxia leads to decreased AC6 expression without altering Gαi/Gαs/T2R14 compared to wild‐type controls. Hypoxia induced ligand and oxygen dependent effects on T2R14 functional responses to fungal QSMs, farnesol, and tyrosol. IL‐5 release was increased in QSM treated CF cells at 1% oxygen. Severe hypoxia inhibited forskolin‐induced currents due to CFTR and reduced cAMP. These results demonstrate expression level and functional alterations due to hypoxia in airway epithelia, including evidence that reduced AC6 expression and function in severe hypoxia is associated with CFTR dysfunction, establishing a potential link between these proteins and the functional outcome of airway epithelial response to hypoxia.
Funding Information
  • Cystic Fibrosis Foundation (003100G221)
  • Natural Sciences and Engineering Research Council of Canada (RGPIN–2020‐05670)

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