i is required for carvedilol-induced β1 adrenergic receptor β-arrestin biased signaling

Nat Commun. 2017 Nov 22;8(1):1706. doi: 10.1038/s41467-017-01855-z.

Abstract

The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein β-arrestin. Some βAR ligands, such as carvedilol, stimulate βAR signaling preferentially through β-arrestin, a concept known as β-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gαs-coupled receptor, whereby carvedilol induces the transition of the β1AR from a classical Gαs-coupled receptor to a Gαi-coupled receptor stabilizing a distinct receptor conformation to initiate β-arrestin-mediated signaling. Recruitment of Gαi is not induced by any other βAR ligand screened, nor is it required for β-arrestin-bias activated by the β2AR subtype of the βAR family. Our findings demonstrate a previously unrecognized role for Gαi in β1AR signaling and suggest that the concept of β-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Carbazoles / pharmacology*
  • Carvedilol
  • Female
  • GTP-Binding Protein alpha Subunits, Gi-Go / deficiency
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Ligands
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Knockout
  • Propanolamines / pharmacology*
  • Protein Conformation / drug effects
  • Receptors, Adrenergic, beta-1 / chemistry
  • Receptors, Adrenergic, beta-1 / metabolism*
  • beta-Arrestins / antagonists & inhibitors
  • beta-Arrestins / genetics
  • beta-Arrestins / metabolism*

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic beta-Antagonists
  • Carbazoles
  • Ligands
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • beta-Arrestins
  • Carvedilol
  • GTP-Binding Protein alpha Subunits, Gi-Go