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Biased Signaling of the G-Protein-Coupled Receptor β 2 AR Is Governed by Conformational Exchange Kinetics

Structure, ISSN: 0969-2126, Vol: 28, Issue: 3, Page: 371-377.e3
2020
  • 37
    Citations
  • 0
    Usage
  • 89
    Captures
  • 0
    Mentions
  • 33
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    37
  • Captures
    89
  • Social Media
    33
    • Shares, Likes & Comments
      33
      • Facebook
        33

Article Description

G-protein-coupled receptors (GPCRs) mediate a wide range of human physiological functions by transducing extracellular ligand binding events into intracellular responses. GPCRs can activate parallel, independent signaling pathways mediated by G proteins or β-arrestins. Whereas “balanced” agonists activate both pathways equally, “biased” agonists dominantly activate one pathway, which is of interest for designing GPCR-targeting drugs because it may mitigate undesirable side effects. Previous studies demonstrated that β-arrestin activation is associated with transmembrane helix VII (TM VII) of GPCRs. Here, single-molecule fluorescence spectroscopy with the β 2 -adrenergic receptor (β 2 AR) in the ligand-free state showed that TM VII spontaneously fluctuates between one inactive and one active-like conformation. The presence of the β-arrestin-biased agonist isoetharine prolongs the dwell time of TM VII in the active-like conformation compared with the balanced agonist formoterol, suggesting that ligands can induce signaling bias by modulating the kinetics of receptor conformational exchange.

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