Study Reveals New Mechanism for GPCR Signaling, Opening Door to Novel Drug Targets
A study published in Nature by researchers at Duke University School of Medicine has identified a new mechanism by which G protein–coupled receptors (GPCRs) control cellular signaling. GPCRs are targets of approximately one-third of FDA-approved drugs.
The Discovery: Liquid-Like Clusters
The researchers found that β-arrestin proteins, which regulate GPCR activity, can assemble into liquid-like clusters called condensates. These condensates form both at baseline and near activated receptors. They act as hubs that organize signaling molecules in space and time.
A New Way Receptors Signal
According to senior author Sudarshan Rajagopal, MD, PhD, associate professor of medicine, the findings show that these receptors signal in a previously unappreciated way. This suggests new potential druggable targets for GPCR signaling.
Methodology and Key Findings
The researchers combined imaging, protein interaction assays, and functional studies. MD-PhD student Preston Anderson conducted the work for his PhD thesis. They demonstrated that disrupting these condensates altered GPCR signaling and receptor internalization, linking the structures directly to function.
Implications for Medicine
The findings help explain how two β-arrestin proteins can regulate hundreds of GPCRs. They point to condensates as a new mechanism for fine-tuning cellular communication.
GPCRs are involved in conditions including shock, heart disease, and asthma. The study suggests new strategies for designing more targeted therapies.
Funding and Authors
Funding was provided by the American Heart Association, the Mandel Foundation, and the National Institutes of Health.
Other Duke authors include: Adam Kaakati, Juliana Alfonso-DeSouza, Alejandra Patino, Andrew Ahn, Chanpreet Jassal, Samuel Liu, Biswaranjan Pani, Athmika Krishnan, Oscar Chen, Joseph Strawn, and Joshua C. Snyder.