Abstract:
:Bronchoconstrictive airway disorders such as asthma are characterized by inflammation and increases in reactive oxygen species (ROS), which produce a highly oxidative environment. β2-adrenergic receptor (β2AR) agonists are a mainstay of clinical therapy for asthma and provide bronchorelaxation upon inhalation. We have previously shown that β2AR agonism generates intracellular ROS, an effect that is required for receptor function, and which post-translationally oxidizes β2AR cysteine thiols to Cys-S-sulfenic acids (Cys-S-OH). Furthermore, highly oxidative environments can irreversibly oxidize Cys-S-OH to Cys-S-sulfinic (Cys-SO2H) or S-sulfonic (Cys-SO3H) acids, which are incapable of further participating in homeostatic redox reactions (i.e., redox-deficient). The aim of this study was to examine the vitality of β2AR-ROS interplay and the resultant functional consequences of β2AR Cys-redox in the receptors native, oxidized, and redox-deficient states. Here, we show for the first time that β2AR can be oxidized to Cys-S-OH in situ, moreover, using both clonal cells and a human airway epithelial cell line endogenously expressing β2AR, we show that receptor redox state profoundly influences β2AR orthosteric ligand binding and downstream function. Specifically, homeostatic β2AR redox states are vital toward agonist-induced cAMP formation and subsequent CREB and G-protein-dependent ERK1/2 phosphorylation, in addition to β-arrestin-2 recruitment and downstream arrestin-dependent ERK1/2 phosphorylation and internalization. On the contrary, redox-deficient β2AR states exhibit decreased ability to signal via either Gαs or β-arrestin. Together, our results demonstrate a β2AR-ROS redox axis, which if disturbed, interferes with proper receptor function.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Rambacher KM,Moniri NHdoi
10.1038/s41598-020-59983-4subject
Has Abstractpub_date
2020-02-19 00:00:00pages
2934issue
1issn
2045-2322pii
10.1038/s41598-020-59983-4journal_volume
10pub_type
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