O-glycosylation and N-terminal cleavage in beta1-adrenergic receptor processing and function
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Auditorium P117 (Aapistie 5 B), Kontinkangas campus
Topic of the dissertation
O-glycosylation and N-terminal cleavage in beta1-adrenergic receptor processing and function
Doctoral candidate
Master of Science Hanna Tuhkanen
Faculty and unit
University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine and Internal Medicine
Subject of study
Medicine
Opponent
Professor Jyrki Kukkonen, University of Helsinki
Custos
Docent Ulla Petäjä-Repo, University of Oulu
GalNAc-transferase 2-mediated regulation of beta1-adrenergic receptor function
Cardiovascular diseases are the leading cause of death in Finland and worldwide. The human beta1-adrenergic receptor is expressed in cardiac myocytes, mediating the sympathetic activation of the heart. The signaling of beta1-adrenergic receptor is dysregulated in several cardiac diseases, such as coronary artery disease and heart failure, which are treated with beta-blockers that inhibit the activity of these receptors.
After synthesis, the beta1-adrenergic receptor is modified by the addition of sugar moieties to its extracellular amino (N)-terminal domain and by proteolytic cleavage. This study investigated how receptor glycosylation and proteolytic processing affect its function and regulation. The study employed biochemical methods as well as mammalian cell models and a rat model.
The results demonstrated that glycosylation of the beta1-adrenergic receptor is mediated by GalNAc-transferase 2 enzyme. Impaired receptor glycosylation was found to lead to increased proteolytic cleavage, which in turn decreased receptor-mediated signaling. In addition, three single-nucleotide polymorphisms of the human beta1-adrenergic receptor—Ser49Gly, Ala29Thr, and Arg31Gln—were shown to regulate receptor function and the number of receptors at the cell surface. The Thr29 variant introduces and the Gly49 variant removes a glycosylation site, whereas the Gln31 variant completely abolishes the receptor cleavage site.
In GalNAc-transferase 2 knockout rats, the changes induced by chronic sympathetic stimulation, including increased cardiac contractility, harmful hypertrophy and fibrotic remodeling, were markedly attenuated. These findings indicate that impaired beta1-adrenergic receptor glycosylation and attenuated receptor-mediated signaling protect the heart against pathological remodeling during chronic sympathetic stress.
This study advances our understanding of beta1-adrenergic receptor regulation by highlighting the functional role of glycosylation. Improved insight into these regulatory mechanisms may aid the development of more effective pharmacological therapies.
After synthesis, the beta1-adrenergic receptor is modified by the addition of sugar moieties to its extracellular amino (N)-terminal domain and by proteolytic cleavage. This study investigated how receptor glycosylation and proteolytic processing affect its function and regulation. The study employed biochemical methods as well as mammalian cell models and a rat model.
The results demonstrated that glycosylation of the beta1-adrenergic receptor is mediated by GalNAc-transferase 2 enzyme. Impaired receptor glycosylation was found to lead to increased proteolytic cleavage, which in turn decreased receptor-mediated signaling. In addition, three single-nucleotide polymorphisms of the human beta1-adrenergic receptor—Ser49Gly, Ala29Thr, and Arg31Gln—were shown to regulate receptor function and the number of receptors at the cell surface. The Thr29 variant introduces and the Gly49 variant removes a glycosylation site, whereas the Gln31 variant completely abolishes the receptor cleavage site.
In GalNAc-transferase 2 knockout rats, the changes induced by chronic sympathetic stimulation, including increased cardiac contractility, harmful hypertrophy and fibrotic remodeling, were markedly attenuated. These findings indicate that impaired beta1-adrenergic receptor glycosylation and attenuated receptor-mediated signaling protect the heart against pathological remodeling during chronic sympathetic stress.
This study advances our understanding of beta1-adrenergic receptor regulation by highlighting the functional role of glycosylation. Improved insight into these regulatory mechanisms may aid the development of more effective pharmacological therapies.
Created 27.4.2026 | Updated 27.4.2026