Efficient and exclusive recognition of nonself requires quality control mechanisms to eliminate self-signaling in various types of organisms and cells. Here, we discovered a previously unknown mechanism, which inactivates self-reactive G protein–coupled receptor (GPCR) used in premating communication between the two mating types of budding yeast. Our results suggest that this mechanism of cell-internal autocrine inactivation involves receptor interaction with its cosecreted peptide ligand within