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

Jeffrey S. Smith, Thomas F. Pack, Asuka Inoue, Claudia Lee, Xinyu Xiong, Kevin Zheng, Alem W. Kahsai, Issac Choi, Zhiyuan Ma, Ian M. Levitan, Lauren K. Rochelle, Dean P. Staus, Joshua C. Snyder, Marc G. Caron, Sudarshan Rajagopal

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalUnknown Journal
Publication statusPublished - 2019 May 7

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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