Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Ga protein subtypes and b-arrestin adaptor proteins. G protein-mediated signaling and b-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between Gai protein subtype family members and b-arrestins regardless of their canonical Ga protein subtype coupling. Gai:b-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with b-arrestins requiring a functional interaction with Gai for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gai:b-arrestin signaling complexes.
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