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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,9,16]]},"abstract":"<jats:p>\n                    The \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -adrenergic receptor (\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR), a prototype G protein\u2013coupled receptor, controls cardiopulmonary function underpinning O\n                    <jats:sub>2<\/jats:sub>\n                    delivery. Abundance of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR is canonically regulated by G protein\u2013coupled receptor kinases and \u03b2-arrestins, but neither controls constitutive receptor levels, which are dependent on ambient O\n                    <jats:sub>2<\/jats:sub>\n                    . Basal \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR expression is instead regulated by the prolyl hydroxylase\/pVHL-E3 ubiquitin ligase system, explaining O\n                    <jats:sub>2<\/jats:sub>\n                    responsivity. Interplay between O\n                    <jats:sub>2<\/jats:sub>\n                    and nitric oxide (NO, a potent bronchodilator) is central to cardiopulmonary function. Here, we demonstrate that pVHL-mediated \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR degradation is counteracted by NO, revealing pVHL control of pulmonary function. NO S-nitrosylates Cys77 in human pVHL (cognate to mouse Cys43), which induces binding of the E3 ubiquitin ligase c-Cbl to degrade pVHL, thereby increasing \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR expression. pVHL\u2013C43S mutant mice refractory to S-nitrosylation exhibit decreases in \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR signaling and increases in airway tone. Thus, pVHL controls adrenergic pulmonary function and contributes to bronchodilation by NO. Our findings suggest therapeutic approaches to asthma and obstructive airway disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2515326122","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:36:41Z","timestamp":1757432201000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["S-nitrosylation of pVHL regulates \u03b2\n                    <sub>2<\/sub>\n                    adrenergic receptor function"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3820-2049","authenticated-orcid":false,"given":"Zachary W.","family":"Grimmett","sequence":"first","affiliation":[{"name":"Medical Scientist Training Program, Case Western Reserve University School of Medicine","place":["Cleveland"]},{"name":"Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine","place":["Cleveland"]},{"name":"Department of Pathology, Case Western Reserve University School of Medicine","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-8719","authenticated-orcid":false,"given":"Thomas M.","family":"Raffay","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Case Western Reserve University School of Medicine","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-5026","authenticated-orcid":false,"given":"Richard T.","family":"Premont","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine","place":["Cleveland"]},{"name":"Harrington Discovery Institute, University Hospitals Cleveland Medical Center","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6866-1572","authenticated-orcid":false,"given":"Jonathan S.","family":"Stamler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine","place":["Cleveland"]},{"name":"Harrington Discovery Institute, University Hospitals Cleveland Medical Center","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(95)00018-2"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/415206a"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.supplement_2.13tac110"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000444"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.14.1634"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62854"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7403"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.046"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.05.024"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.03.034"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","unstructured":"G. Wang N. H. Moniri K. Ozawa J. S. Stamler Y. Daaka Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc. Natl. Acad. Sci. U.S.A. 103 1295\u20131300 (2006).","DOI":"10.1073\/pnas.0508354103"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","unstructured":"F. Beigi Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proc. Natl. Acad. Sci. 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Grimmett The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming. bioRxiv [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.03.12.642752 (Accessed 4 August 2025).","DOI":"10.7554\/eLife.106601"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.4.1564"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1159\/000362684"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2515326122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T15:37:39Z","timestamp":1757432259000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2515326122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":74,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2025,9,16]]}},"alternative-id":["10.1073\/pnas.2515326122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2515326122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,9]]},"assertion":[{"value":"2025-06-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2515326122"}}