Location-biased β-arrestin conformations direct GPCR signaling

Area of Science:

• Cellular signaling
• Molecular biology
• Pharmacology

Background:

• Beta-arrestins (β-arrestins) are key regulators of G protein-coupled receptor (GPCR) function, mediating desensitization, internalization, and signaling.
• GPCRs can signal from various subcellular locations, a phenomenon termed 'location bias', leading to diverse cellular responses.
• The specific roles of β-arrestins in directing this location-biased signaling remain incompletely understood.

Purpose of the Study:

• To investigate how β-arrestins mediate location-biased signaling of the angiotensin II type I receptor (AT1R).
• To elucidate the distinct conformations and subcellular activities of β-arrestin 1 and β-arrestin 2 in response to different agonists.
• To uncover novel mechanisms of β-arrestin-mediated signaling independent of G proteins.

Main Methods:

• Utilized bioluminescence resonance energy transfer (BRET) conformational biosensors to monitor β-arrestin conformations.
• Employed extracellular signal-regulated kinase (ERK) activity reporters to assess signaling dynamics.
• Investigated receptor-free β-arrestin activity at the plasma membrane.

Main Results:

• β-arrestin 1 and β-arrestin 2 adopt distinct conformations in different subcellular locations in response to Angiotensin II and TRV023.
• These distinct conformations correlate with differential ERK activation profiles.
• A population of catalytically active, receptor-free β-arrestins was identified at the plasma membrane, promoting G protein-independent ERK activation.

Conclusions:

• β-arrestins play a crucial role in directing location-biased GPCR signaling through conformational changes.
• Receptor-free β-arrestins contribute to signaling complexity at the plasma membrane.
• These findings expand the understanding of β-arrestin functions beyond canonical G protein-dependent pathways.