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


  • M. Park
  • G.R. Reddy
  • G. Wallukat
  • Y.K. Xiang
  • S.F. Steinberg


  • Scientific Reports


  • Sci Rep 7 (1): 7890


  • {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.