Noncanonical scaffolding of Gai and b-arrestin by G protein-coupled receptors

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

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Ga protein subtypes and b-arrestin adaptor proteins. G protein-mediated signaling and b-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between Gai protein subtype family members and b-arrestins regardless of their canonical Ga protein subtype coupling. Gai:b-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with b-arrestins requiring a functional interaction with Gai for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gai:b-arrestin signaling complexes.

Original languageEnglish
Article numbereaay1833
Issue number6534
Publication statusPublished - 2021 Mar 12

ASJC Scopus subject areas

  • General


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