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| Item Type: | Article |
|---|---|
| Title: | β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes |
| Creators Name: | Park, M., Reddy, G.R., Wallukat, G., Xiang, Y.K. and Steinberg, S.F. |
| Abstract: | {beta}1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the {beta}1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the {beta}1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies {beta}1AR N-terminal O-glycosylation at Ser(37)/Ser(41) as a mechanism that prevents {beta}1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated {beta}1ARs and N-terminally truncated glycosylation-defective {beta}1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes {beta}1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of {beta}1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage. |
| Keywords: | Adenoviridae, beta-1 Adrenergic Receptors, Cardiac Myocytes, Catecholamines, Cultured Cells, Gene Expression, Genetic Vectors, Glycosylation, Newborn Animals, Proteolysis, Signal Transduction, Animals, Wistar Rats |
| Source: | Scientific Reports |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Volume: | 7 |
| Number: | 1 |
| Page Range: | 7890 |
| Date: | 11 August 2017 |
| Official Publication: | https://doi.org/10.1038/s41598-017-06607-z |
| PubMed: | View item in PubMed |
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