GPR3 (G protein-coupled receptor 3) is a constitutively active orphan G protein-coupled receptor that maintains elevated intracellular cAMP levels through continuous Gs-coupling activity, even in the absence of exogenous ligands 1. The receptor's constitutive activity is conferred by its N-terminus, making transcriptional regulation of Gpr3 expression functionally equivalent to ligand-binding in conventional GPCRs 1. GPR3 plays essential roles in thermogenic adipocyte function, where it drives energy expenditure and counteracts metabolic disease through lipolysis-induced expression 1. In Kupffer cells, GPR3 activation stimulates glycolysis via β-arrestin2-PKM2 pathway formation, protecting against obesity and fatty liver disease 2. The receptor functions through both G protein-mediated and non-G protein-mediated mechanisms 3 and can form constitutive homodimers with unique oligomerization-modulated signaling properties 4. GPR3 is implicated in reproductive function, as rare variants are associated with premature ovarian insufficiency 5, and it plays a role in oocyte meiotic arrest 6. The receptor shows promise as a therapeutic target for metabolic diseases, central nervous system disorders, and has been identified as a target for cannabidiol as an inverse agonist 3.