PT  - JOURNAL ARTICLE
AU  - Jeffrey S. Smith
AU  - Thomas F. Pack
AU  - Asuka Inoue
AU  - Claudia Lee
AU  - Xinyu Xiong
AU  - Kevin Zheng
AU  - Alem W. Kahsai
AU  - Issac Choi
AU  - Zhiyuan Ma
AU  - Ian M. Levitan
AU  - Lauren K. Rochelle
AU  - Dean P. Staus
AU  - Joshua C. Snyder
AU  - Marc G. Caron
AU  - Sudarshan Rajagopal
TI  - Noncanonical scaffolding of G<sub>αi</sub> and β-arrestin by G protein-coupled receptors
AID  - 10.1101/629576
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 629576
4099  - http://biorxiv.org/content/early/2019/05/07/629576.short
4100  - http://biorxiv.org/content/early/2019/05/07/629576.full
AB  - 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 Gα proteins, such as Gαs, Gαi, Gαq or Gα12/13, 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 Gα proteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαi protein family members and β-arrestin. Gαi: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 Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.