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

Significance In complex biological systems, cells are constantly exposed to multiple physical and chemical stimuli. To decode such diverse inputs, cells use proteins embedded in the membrane to distinguish signal from noise and mount appropriate cellular responses. G protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors in humans with more than 800 unique members. Here, we show that many GPCRs function as molecular coincidence detectors that couple proton (H + ) binding to receptor agonism. Our findings provide insights into the fundamentals of GPCR signaling and avenues for exploring GPCR responses to coincident H + signals generated by a variety of biological processes and pathological scenarios.