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We have previously shown that \u03b22AR agonism generates intracellular ROS, an effect that is required for receptor function, and which post-translationally oxidizes \u03b22AR 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-SO<jats:sub>2<\/jats:sub>H) or S-sulfonic (Cys-SO<jats:sub>3<\/jats:sub>H) 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 \u03b22AR-ROS interplay and the resultant functional consequences of \u03b22AR Cys-redox in the receptors native, oxidized, and redox-deficient states. Here, we show for the first time that \u03b22AR can be oxidized to Cys-S-OH <jats:italic>in situ<\/jats:italic>, moreover, using both clonal cells and a human airway epithelial cell line endogenously expressing \u03b22AR, we show that receptor redox state profoundly influences \u03b22AR orthosteric ligand binding and downstream function. Specifically, homeostatic \u03b22AR redox states are vital toward agonist-induced cAMP formation and subsequent CREB and G-protein-dependent ERK1\/2 phosphorylation, in addition to \u03b2-arrestin-2 recruitment and downstream arrestin-dependent ERK1\/2 phosphorylation and internalization. On the contrary, redox-deficient \u03b22AR states exhibit decreased ability to signal via either G\u03b1s or \u03b2-arrestin. Together, our results demonstrate a \u03b22AR-ROS redox axis, which if disturbed, interferes with proper receptor function.<\/jats:p>","DOI":"10.1038\/s41598-020-59983-4","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T11:03:30Z","timestamp":1582110210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cysteine redox state regulates human \u03b22-adrenergic receptor binding and function"],"prefix":"10.1038","volume":"10","author":[{"given":"Kalyn M.","family":"Rambacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader H.","family":"Moniri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"59983_CR1","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.mam.2018.08.001","volume":"63","author":"A van der Vliet","year":"2018","unstructured":"van der Vliet, A., Janssen-Heininger, Y. 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