?1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes.

ABSTRACT: ?1-adrenergic receptors (?1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the ?1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the ?1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies ?1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents ?1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated ?1ARs and N-terminally truncated glycosylation-defective ?1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes ?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 ?1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.

SUBMITTER: Park M 

PROVIDER: S-EPMC5554155 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature