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Location-biased β-arrestin conformations direct GPCR signaling
Uyen Pham1, Anand Chundi2, Tomasz M Stępniewski3,4
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
Science Signaling
|March 24, 2026
Summary
Beta-arrestins (β-arrestins) direct location-biased signaling of G protein-coupled receptors (GPCRs). Distinct β-arrestin conformations in different cellular locations influence signaling pathways like ERK.
Area of Science:
- Cellular Biology
- Molecular Pharmacology
- Biochemistry
Background:
- Beta-arrestins (β-arrestins) are key regulators of G protein-coupled receptor (GPCR) function, involved in desensitization, internalization, and signaling.
- GPCRs can signal from various subcellular locations, a phenomenon termed 'location bias', leading to distinct signaling outcomes.
Purpose of the Study:
- To investigate how β-arrestins mediate location-biased signaling of the angiotensin II type 1 receptor (AT1R).
- To explore the distinct conformations and signaling roles of β-arrestin 1 and β-arrestin 2 in different subcellular compartments.
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 AT1R signaling in response to angiotensin II and a β-arrestin-biased agonist (TRV023).
Main Results:
- β-arrestin 1 and β-arrestin 2 adopted distinct conformations in different subcellular locations upon AT1R activation.
- These distinct conformations correlated with differential ERK activation profiles.
- Identified receptor-free, activated β-arrestins at the plasma membrane, promoting G protein-independent ERK activation.
Conclusions:
- β-arrestins play nuanced roles in directing GPCR location-biased signaling beyond canonical G protein pathways.
- The conformation and subcellular location of β-arrestins are critical determinants of specific signaling outcomes.
- Findings advance the understanding of GPCR signaling complexity and β-arrestin function.
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