Molecular mechanisms and therapeutic potential of proton-sensing GPCRs

Extracellular acidification is a defining feature of many pathological microenvironments and is sensed by G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68. These proton-sensing receptors regulate vascular, immune, and neural responses and are increasingly implicated in inflammation, cancer, fibrosis, and ischemic injury. Recent cryo-electron microscopy structures have revealed the molecular basis of proton detection, highlighting dynamic extracellular loop rearrangements, pH-sensitive histidine networks, and a stepwise activation mechanism that tunes G protein coupling and signaling bias. Emerging structural evidence also shows lipid modulation and species-specific adaptations that shape receptor responsiveness. These advances provide a structural and mechanistic framework for developing selective modulators of proton-sensing GPCRs as therapeutic targets in acidic disease environments.