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 Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins regardless of their canonical Gα protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.
Smith, JS; Pack, TF; Inoue, A; Lee, C; Zheng, K; Choi, I; Eiger, DS; Warman, A; Xiong, X; Ma, Z; Viswanathan, G; Levitan, IM; Rochelle, LK; Staus, DP; Snyder, JC; Kahsai, AW; Caron, MG; Rajagopal, S
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