Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias

Kouki Kawakami, Masataka Yanagawa, Suzune Hiratsuka, Misaki Yoshida, Yuki Ono, Michio Hiroshima, Masahiro Ueda, Junken Aoki, Yasushi Sako () and Asuka Inoue ()
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Kouki Kawakami: Tohoku University
Masataka Yanagawa: RIKEN Cluster for Pioneering Research
Suzune Hiratsuka: Tohoku University
Misaki Yoshida: Tohoku University
Yuki Ono: Tohoku University
Michio Hiroshima: RIKEN Cluster for Pioneering Research
Masahiro Ueda: Laboratory for Cell Signaling Dynamics, RIKEN BDR
Junken Aoki: The University of Tokyo
Yasushi Sako: RIKEN Cluster for Pioneering Research
Asuka Inoue: Tohoku University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Signaling-biased ligands acting on G-protein-coupled receptors (GPCRs) differentially activate heterotrimeric G proteins and β-arrestins. Although a wealth of structural knowledge about signaling bias at the GPCR level exists (preferential engagement of a specific transducer), little is known about the bias at the transducer level (different functions mediated by a single transducer), partly due to a poor understanding of GPCR kinase (GRK)-mediated GPCR phosphorylation. Here, we reveal a unique role of the Gq heterotrimer as a determinant for GRK-subtype selectivity that regulates subsequent β-arrestin conformation and function. Using the angiotensin II (Ang II) type-1 receptor (AT1R), we show that β-arrestin recruitment depends on both GRK2/3 and GRK5/6 upon binding of Ang II, but solely on GRK5/6 upon binding of the β-arrestin-biased ligand TRV027. With pharmacological inhibition or genetic loss of Gq, GRK-subtype selectivity and β-arrestin functionality by Ang II is shifted to those of TRV027. Single-molecule imaging identifies relocation of AT1R and GRK5, but not GRK2, to an immobile phase under the Gq-inactive, AT1R-stimulated conditions. These findings uncover a previously unappreciated Gq-regulated mechanism that encodes GRK-subtype selectivity and imparts distinct phosphorylation-barcodes directing downstream β-arrestin functions.

Date: 2022
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DOI: 10.1038/s41467-022-28056-7

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