β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes

Misun Park, Gopireddy R. Reddy, Gerd Wallukat, Yang Kevin Xiang, Susan F. Steinberg

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

β1-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 β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of β1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.

Original languageEnglish (US)
Article number7890
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

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