Year: 2026
Type: article
Abstract: G protein-coupled receptors (GPCRs) are targets for almost a third of all FDA-approved drugs. GPCRs are known to signal through both heterotrimeric G proteins and β-arrestins. Traditionally these pathways were viewed as largely separable, with G proteins primarily initiating downstream signaling while β-arrestins modulate receptor trafficking and desensitization in addition to regulating their own signaling events. Recent studies suggest an integrated role of G proteins and β-arrestins in GPCR signaling, however the cellular and biochemical requirements for G protein:β-arrestin interactions remain unclear. Here, we show that G proteins and β-arrestins can directly interact. Through utilization of β-arrestin-biased receptors and artificially enforced β-arrestin relocalization, we demonstrate that recruitment of β-arrestin to the plasma membrane is sufficient to interact with the G protein Gαi. Using purified proteins, we show that Gαi directly interacts with β-arrestin. In addition, we find that Gαi family members differ in their degree of association with β-arrestin, and that a large degree of this selectivity resides within the alpha helical domain of Gαi. These findings delineate the cellular and biochemical conditions that drive direct interactions between G proteins and β-arrestins and illuminate the molecular basis for how they interact.
Source: Nature Communications
Authors: Claudia Y. Lee, Jeffrey S. Smith, Taylor Kohlmann, Emily M. Meara, Uyen Pham, Frank Kwarcinski, Andrew N. Dates, Jessica K. Orofino, Issac Choi, Ari S. Hilibrand, Chanpreet Jassal, Abigail Gilmer, Stephen C. Blacklow, Gregory G. Tall, Andrew C. Kruse, Sudarshan Rajagopal
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: American Heart Association, Richard and Susan Smith Family Foundation, Harvard University, RTI International, North Carolina Central University, Fujifilm Corporation, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Functional divergence of ß-arrestin isoforms drives distinct AT1R signaling in hypertension, Defining the Role of of Noncanonical GPCR Signalling in Pulmonary Hypertension, Making antibody generation rapid, scalable, and democratic through machine learning and continuous evolution, Biochemical Determinants of Chemokine Receptor Signaling, Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins, Biasing CXCR3 Signaling to Modulate the Inflammatory Response
OpenAlex ID: W4411864768