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

Nat Commun. 2022 Jan 25;13(1):487. doi: 10.1038/s41467-022-28056-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Cell Line
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • G-Protein-Coupled Receptor Kinase 5 / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Humans
  • Oligopeptides / pharmacology*
  • Phosphorylation
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Signal Transduction
  • Vasoconstrictor Agents / pharmacology
  • beta-Arrestins / metabolism*


  • AGTR1 protein, human
  • Oligopeptides
  • Receptor, Angiotensin, Type 1
  • Vasoconstrictor Agents
  • beta-Arrestins
  • Angiotensin II
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH