G protein-coupled receptor 4 (GPR4)

G protein-coupled receptor 4 (GPR4) is a member of the proton-sensing G protein-coupled receptor family, primarily activated by extracellular protons in the physiological pH range (optimal pH 6.8–7.2). Upon activation, GPR4 couples mainly to the Gs family of G proteins, increasing adenylate cyclase activity and intracellular cAMP, and can also signal through Gq and G12/13. GPR4 regulates adaptive responses to acidotic stress, including acid-base balance in the kidney, vascular endothelial permeability, and the drive to breathe by detecting protons generated from CO₂ in the blood. Overactivation of GPR4 is implicated in the acidic tumor microenvironment and inflamed tissues, supporting roles in cancer progression and inflammation. Its unique activation by pH makes it a target of interest for therapeutic modulation, though targeting GPR4 carries risk for systemic acid–base and vascular disturbances.

Other names

GPR4G-protein coupled receptor 4hGPR4GPR6C.lG-protein coupled receptor 6C.lG-protein coupled receptor 19

Activation by extracellular protons (pH 6.8–7.2) induces conformational change and G protein coupling (mainly Gs, also Gq and G12/13), resulting in activation of adenylate cyclase and cAMP production. Modulation of Rho GTPase pathway, impacting vascular permeability. Drugs would block (antagonists) or mimic (agonists) proton-dependent activation.