GPR4 is a proton-sensing G protein-coupled receptor that functions as a cellular pH sensor for detecting extracellular acidification 1. The receptor is optimally activated at pH 6.8-7.2 and contains critical extracellular histidine residues that directly sense proton concentrations, triggering conformational changes in extracellular loop 2 that propagate to transmembrane domains 234. GPR4 primarily couples to Gs proteins to activate adenylate cyclase signaling, though it can also interact with Gi, Gq, and G12/G13 proteins 1. Mechanistically, proton binding establishes hydrogen bond networks and hydrophobic rearrangements that enable G protein coupling 3. GPR4 plays critical physiological roles in respiratory chemoreception, where it detects CO2-derived protons in brainstem retrotrapezoid nucleus neurons to regulate breathing 56. The receptor also regulates acid-base homeostasis in the kidney collecting duct and modulates vascular endothelial permeability during acidosis through G12/G13/Rho signaling 1. GPR4 contributes to multiple pathological processes including tumor biology, cardiovascular dysfunction, and asthma, making it a potential therapeutic target for pH-related diseases 1.