Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

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