Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifications (PTMs) remains largely unexplored. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G-protein activity that is emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. After profiling the N-glycosylation and phosphorylation patterns, we found that these two types of PTMs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive G