What is the clinical evidence from this study?

Study design: Other. Population: GPCR signaling. Intervention: Angiotensin II and TRV023. Primary outcome: β-arrestin conformation and ERK activation profiles.

What question did this study set out to answer?

The research aims to understand how β-arrestins influence location-specific signaling of GPCRs, particularly AT1R.

March 26, 2026

Location-biased β-arrestin conformations direct GPCR signaling

Key Result

β-arrestin 1 and 2 adopted distinct conformations across subcellular locations in response to agonists, directing location-biased signaling of the AT1R and promoting ERK activation.

Key Points

The research aims to understand how β-arrestins influence location-specific signaling of GPCRs, particularly AT1R.
Used bioluminescence resonance energy transfer (BRET) to assess β-arrestin conformations.
Utilized ERK activity reporters to measure signaling outcomes.
Explored the responses to angiotensin II and TRV023 on β-arrestin conformations across various locations.
Identified that β-arrestin 1 and β-arrestin 2 adopt distinct conformations based on subcellular location.
Found receptor-free β-arrestins activating ERK at the plasma membrane without G protein involvement.
Demonstrated that different agonists lead to varying ERK activation profiles depending on β-arrestin conformation.

Structured PICO

Intervention

Angiotensin II and TRV023 (β-arrestin–biased agonist)

Outcome

β-arrestin conformations and extracellular signal–regulated kinase (ERK) activation profiles across subcellular locationssurrogate

The study reveals that β-arrestins adopt location-specific conformations that direct distinct ERK signaling profiles, highlighting their nuanced roles beyond traditional G protein pathways.

Abstract

β-Arrestins are multifunctional, intracellular proteins that regulate the desensitization, internalization, and signaling of more than 800 G protein–coupled receptors (GPCRs) and interact with a diverse array of intracellular partners. Beyond the plasma membrane, GPCRs can initiate distinct signaling cascades from various subcellular locations, a phenomenon known as “location bias.” Here, we investigated how β-arrestins directed location-biased signaling of the angiotensin II type 1 receptor (AT1R) using bioluminescence resonance energy transfer (BRET) conformational biosensors and extracellular signal–regulated kinase (ERK) activity reporters. We found that, in response to the endogenous agonist angiotensin II and the β-arrestin–biased agonist TRV023, β-arrestin 1 and β-arrestin 2 adopted distinct conformations across different subcellular locations, which were associated with different ERK activation profiles. We also uncovered a population of receptor-free, activated β-arrestins in the plasma membrane that exhibited insensitivity to different agonists and promoted ERK activation at the plasma membrane independently of G proteins. These findings deepen our understanding of GPCR signaling complexity and highlight the nuanced roles of β-arrestins beyond traditional G protein pathways.

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