Year: 2026
Type: article
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.
Source: Science Signaling
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: Functional divergence of ß-arrestin isoforms drives distinct AT1R signaling in hypertension, Disección de los fundamentos de la eficacia superior de la clozapina para el tratamiento de la esquizofrenia: desde pruebas moleculares hasta evidencias cerebrales, G8182805480, Biasing CXCR3 Signaling to Modulate the Inflammatory Response
OpenAlex ID: W7140175518