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Papers of the Week

Papers: 6 Feb 2021 - 12 Feb 2021

Pharmacology/Drug Development

2021 Jan 21


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


Smith JS, Pack TF, Inoue A, Lee C, Zheng K, Choi I, Eiger DS, Warman A, Xiong X, Ma Z, Viswanathan G, Levitan IM, Rochelle LK, Staus DP, Snyder JC, Kahsai AW, Caron MG, Rajagopal S
Science. 2021 Jan 21.
PMID: 33479120.


Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific G 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 G protein subtype family members and β-arrestins, regardless of their canonical G protein subtype coupling. G: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 G for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of G:β-arrestin signaling complexes.