Molecular mechanism of pH sensing and activation in GPR4 reveals proton-mediated GPCR signaling.

ABSTRACT: Maintaining pH homeostasis is critical for cellular function across all living organisms. Proton-sensing G protein-coupled receptors (GPCRs), particularly GPR4, play a pivotal role in cellular responses to pH changes. Yet, the molecular mechanisms underlying their proton sensing and activation remain incompletely understood. Here we present high-resolution cryo-electron microscopy structures of GPR4 in complex with G proteins under physiological and acidic pH conditions. Our structures reveal an intricate proton-sensing mechanism driven by a sophisticated histidine network in the receptor's extracellular domain. Upon protonation of key histidines under acidic conditions, a remarkable conformational cascade is initiated, propagating from the extracellular region to the intracellular G prote

SUBMITTER: You C 

PROVIDER: S-EPMC12187918 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature