GPR33 is an orphan G protein-coupled receptor belonging to the chemoattractant receptor family that functions in innate immunity and leukocyte chemotaxis. Structurally, GPR33 contains conserved domains characteristic of rhodopsin-like GPCRs, including a functionally important Asp-Arg-Tyr (DRY) motif in the third transmembrane domain 1. Upon activation, GPR33 couples to multiple canonical signaling pathways including cAMP, Ca2+, MAPK/ERK, and Rho-dependent pathways 2. The receptor is highly expressed in dendritic cells, where its expression is regulated by toll-like receptor activity and AP-1/NF-κB signaling 3. Clinically, GPR33 represents a notable example of recent gene inactivation in human evolution. The receptor underwent independent pseudogenization in humans and other primates within the last 1 million years, likely driven by selective pressure 4. However, the intact GPR33 allele persists in human populations 4. GPR33 was previously proposed as a pathogen entry site 2, suggesting its inactivation may reflect evolutionary adaptation to specific infections. The coincidental pseudogenization across distantly related mammalian species indicates this gene loss was not neutral 4, highlighting GPR33's historical importance in species-specific immune responses.