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Noncanonical scaffolding of Gi and -arrestin by G protein-coupled receptors

Smith, JS;Pack, TF;Inoue, A;Lee, C;Xiong, X;Zheng, K;

G-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct G proteins, such as Gs, Gi, Gq or G12/13, as well as -arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of G proteins to directly interact with -arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gi protein family members and -arrestin. Gi:-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gi:-arrestin scaffolds enhances our understanding of GPCR signalling.