Proton‐gated Coincidence Detection is a Common Feature of GPCR Signaling

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The evolutionary expansion of G protein‐coupled receptors (GPCRs) has produced a rich diversity of transmembrane sensors for many physical and chemical signals. In humans alone, over 800 GPCRs detect stimuli such as light, hormones, and metabolites to guide cellular decision‐making primarily using intracellular G protein signaling networks. This diversity is further enriched by GPCRs that function as molecular sensors capable of discerning multiple inputs to transduce cues encoded in complex, context‐dependent signals. Here, we show that many GPCRs are coincidence detectors that couple proton (H+) binding to GPCR signaling. Using a large panel of receptors covering hundreds of individual GPCR‐Gα coupling combinations, we show that H+ gating both positively and negatively modulates GPCR signaling. Notably, these observations extend to all modes of GPCR pharmacology including ligand efficacy, potency, and cooperativity. Additionally, we show that GPCR antagonism and constitutive activity are regulated by H+ gating and report the discovery of new GPCR H+ sensors that can be activated solely by changes in pH. Together, these findings establish a paradigm for GPCR signaling, biology, and pharmacology applicable to acidified microenvironments such as endosomes, synapses, tumors, and ischemic vasculature.