(R4123) Proton-gated coincidence detection is a common feature of GPCR signaling

Nicholas Kapolka (University of Miami Miller School of Medicine)| Jacob Rowe (University of Miami Miller School of Medicine)| Geoffrey Taghon (University of Miami Miller School of Medicine)| William Morgan (University of Miami Miller School of Medicine)| Corin O'Shea (University of Miami Miller School of Medicine)| Daniel Isom (University of Miami Miller School of Medicine, University of Miami Miller Sylvester Comprehensive Cancer Center, University of Miami Institute for Data Science and Computing)

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 logic gates capable of discerning multiple inputs to transduce cues encoded in complex, context-dependent signals. Here, we show that many GPCRs are switch-like Boolean-gated coincidence detectors that couple proton (H+) binding to GPCR signaling. Using a panel of 28 receptors, covering 280 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 a new acid sensor, the adenosine A2a receptor (ADORA2A), which can be activated solely by acidic pH. Together, these findings establish a new paradigm for GPCR biology and pharmacology in acidified microenvironments such as endosomes, synapses, tumors, and ischemic vasculature.