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Their functional implications are, however, largely unknown. We have previously shown that the human \u03b2<jats:sub>1<\/jats:sub>\u2010adrenergic receptor (\u03b2<jats:sub>1<\/jats:sub>AR) is O\u2010glycosylated in the N\u2010terminal extracellular domain by polypeptide GalNAc transferase\u20102 that co\u2010regulates receptor proteolytic cleavage. Here, we demonstrate that the common S49G and the rare A29T and R31Q SNPs alter these modifications, leading to distinct effects on receptor processing. This was achieved by <jats:italic>in vitro<\/jats:italic> O\u2010glycosylation assays, analysis of native receptor N\u2010terminal O\u2010glycopeptides, and expression of receptor variants in cell lines and neonatal rat ventricular cardiomyocytes deficient in O\u2010glycosylation. The SNPs eliminated (S49G) or introduced (A29T) regulatory O\u2010glycosites that enhanced or inhibited cleavage at the adjacent sites (P<jats:sup>52<\/jats:sup>\u2193L<jats:sup>53<\/jats:sup> and R<jats:sup>31<\/jats:sup>\u2193L<jats:sup>32<\/jats:sup>), respectively, or abolished the major site at R<jats:sup>31<\/jats:sup>\u2193L<jats:sup>32<\/jats:sup> (R31Q). The inhibition of proteolysis of the T29 and Q31 variants correlated with increased full\u2010length receptor levels at the cell surface. Furthermore, the S49 variant showed increased isoproterenol\u2010mediated signaling in an enhanced bystander bioluminescence energy transfer \u03b2\u2010arrestin2 recruitment assay in a coordinated manner with the common C\u2010terminal R389G polymorphism. As Gly at position 49 is ancestral in placental mammals, the results suggest that its exchange to Ser has created a \u03b2<jats:sub>1<\/jats:sub>AR gain\u2010of\u2010function phenotype in humans. This study provides evidence for regulatory mechanisms by which GPCR SNPs outside canonical domains that govern ligand binding and activation can alter receptor processing and function. Further studies on other GPCR SNPs with clinical importance as drug targets are thus warranted.<\/jats:p>","DOI":"10.1111\/febs.17257","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T09:51:18Z","timestamp":1724925078000},"page":"998-1018","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Altered O\u2010glycosylation of \u03b2<sub>1<\/sub>\u2010adrenergic receptor N\u2010terminal single\u2010nucleotide variants modulates receptor processing and functional activity"],"prefix":"10.1111","volume":"292","author":[{"given":"Hanna E.","family":"Tuhkanen","sequence":"first","affiliation":[{"name":"Medical Research Center Oulu and Research Unit of Biomedicine and Internal Medicine University of Oulu  Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona J.","family":"Haasiom\u00e4ki","sequence":"additional","affiliation":[{"name":"Medical Research Center Oulu and Research Unit of Biomedicine and Internal Medicine University of Oulu  Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarkko J.","family":"Lackman","sequence":"additional","affiliation":[{"name":"Medical Research Center Oulu and Research Unit of Biomedicine and Internal Medicine University of Oulu  Finland"},{"name":"Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences University of Copenhagen  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoffer K.","family":"Goth","sequence":"additional","affiliation":[{"name":"Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences University of Copenhagen  Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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