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

Summary 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 α proteins, such as G αs , G αi , G αq or G α12/13 , as well as β-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 α proteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between G αi protein family members and β-arrestin. G αi :β-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 G αi :β-arrestin scaffolds enhances our understanding of GPCR signalling.