GPR52 is a brain-enriched, Gs/olf-coupled orphan GPCR that represents an emerging neurotherapeutic target 1. The receptor exhibits intrinsically high basal activity through a self-activation mechanism, where extracellular loop 2 acts as a built-in agonist occupying the orthosteric binding pocket, with Gs coupling enhancing full activation in the absence of external ligands 2. Post-translational modifications, including N-glycosylation and phosphorylation, differentially regulate GPR52's signaling bias, with N-glycosylation promoting Gs signaling while helix 8 phosphorylation suppresses arrestin recruitment and receptor internalization 3. GPR52 modulates cAMP-dependent physiological processes, including locomotor activity through dopamine and NMDA signaling pathway modulation 1. Regarding disease relevance, GPR52 agonism shows therapeutic promise for schizophrenia and psychiatric disorders, with HTL0048149 advancing to phase I clinical trials 1. Conversely, GPR52 inhibition may benefit Huntington's disease treatment by modulating huntingtin protein accumulation through cAMP-dependent mechanisms 1. Additionally, GPR52 loss correlates with breast cancer progression, increased cell clustering, and collective invasion, suggesting GPR52 agonism as a potential cancer therapeutic approach 4. Recent drug discovery efforts have identified potent, selective G-protein-biased agonists with reduced β-arrestin activity and sustained activation potential 5.