UC Davis

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.