PT  - JOURNAL ARTICLE
AU  - Smith, Jeffrey S.
AU  - Pack, Thomas F.
AU  - Inoue, Asuka
AU  - Lee, Claudia
AU  - Zheng, Kevin
AU  - Choi, Issac
AU  - Eiger, Dylan S.
AU  - Warman, Anmol
AU  - Xiong, Xinyu
AU  - Ma, Zhiyuan
AU  - Viswanathan, Gayathri
AU  - Levitan, Ian M.
AU  - Rochelle, Lauren K.
AU  - Staus, Dean P.
AU  - Snyder, Joshua C.
AU  - Kahsai, Alem W.
AU  - Caron, Marc G.
AU  - Rajagopal, Sudarshan
TI  - Noncanonical scaffolding of G<sub>αi</sub> and β-arrestin by G protein–coupled receptors
AID  - 10.1126/science.aay1833
DP  - 2021 Feb 21
TA  - Science
PG  - eaay1833
4099  - http://science.sciencemag.org/content/early/2021/01/21/science.aay1833.short
4100  - http://science.sciencemag.org/content/early/2021/01/21/science.aay1833.full
AB  - Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein- and β-arrestin-mediated signaling have been considered separable. We show GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins, regardless of their canonical Gαi protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK) and their disruption impaired both ERK activation and cell migration, consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.