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

Author

Listed:
  • 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
    Laboratory for Cell Signaling Dynamics, RIKEN BDR)

  • Masahiro Ueda

    (Laboratory for Cell Signaling Dynamics, RIKEN BDR
    Osaka University)

  • Junken Aoki

    (The University of Tokyo)

  • Yasushi Sako

    (RIKEN Cluster for Pioneering Research)

  • Asuka Inoue

    (Tohoku University)

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.

Suggested Citation

  • Kouki Kawakami & Masataka Yanagawa & Suzune Hiratsuka & Misaki Yoshida & Yuki Ono & Michio Hiroshima & Masahiro Ueda & Junken Aoki & Yasushi Sako & Asuka Inoue, 2022. "Heterotrimeric Gq proteins act as a switch for GRK5/6 selectivity underlying β-arrestin transducer bias," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28056-7
    DOI: 10.1038/s41467-022-28056-7
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    References listed on IDEAS

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    1. Aashish Manglik & Henry Lin & Dipendra K. Aryal & John D. McCorvy & Daniela Dengler & Gregory Corder & Anat Levit & Ralf C. Kling & Viachaslau Bernat & Harald Hübner & Xi-Ping Huang & Maria F. Sassano, 2016. "Structure-based discovery of opioid analgesics with reduced side effects," Nature, Nature, vol. 537(7619), pages 185-190, September.
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    1. Tobias Benkel & Mirjam Zimmermann & Julian Zeiner & Sergi Bravo & Nicole Merten & Victor Jun Yu Lim & Edda Sofie Fabienne Matthees & Julia Drube & Elke Miess-Tanneberg & Daniela Malan & Martyna Szpako, 2022. "How Carvedilol activates β2-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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