Breaking the one-site myth: the multifaceted world of proton sensing in GPCRs

Proton-sensing GPCRs detect extracellular acidification and play a pivotal role in maintaining pH homeostasis, influencing processes such as inflammation, cancer progression, and neuropathic pain. While initially believed to rely solely on histidine protonation for activation, emerging evidence suggests that acidic triads, beyond histidine residues, are crucial for proton sensing. Variations in histidine distribution and sequence composition among these receptors point to distinct activation mechanisms within the proton-sensing GPCR family. This Viewpoint consolidates findings from previously published studies to explore the structural and molecular intricacies of proton recognition, receptor activation, and downstream signaling in proton-sensing GPCRs. By integrating insights from molecular dynamics simulations, evolutionary analysis, structural studies, and functional assays, we highlight the complex and multifaceted nature of GPCRs in proton sensing. Collectively, these studies reveal a previously unrecognized network of critical residues and activation sites, reshaping our understanding of GPCR function. Beyond structural and mechanistic insights, this compilation of findings offers new perspectives on targeting proton-sensing pathways for therapeutic intervention in various diseases.