Duke Researchers Discover GPCRs Signal Through Liquid-Like Protein Condensates, Opening New Avenues for Drug Development
Key Insights
Duke University researchers discovered that G protein-coupled receptors (search) (GPCRs), targets of roughly one-third of FDA-approved drugs, signal through liquid-like protein clusters called biomolecular condensates formed by β-arrestin (search) proteins.
The findings, published in Nature, reveal an unexpected mechanism that could enable more precise control of GPCR activity and open new avenues for drug development.
When scientists disrupted the condensates, GPCR signaling was disrupted, demonstrating that β-arrestin (search) clustering directly influences how these critical receptors function.
A groundbreaking study from Duke University School of Medicine has revealed that G protein-coupled receptors (search) (GPCRs) — the targets of roughly one-third of all FDA-approved drugs — signal through liquid-like protein clusters known as biomolecular condensates, an unexpected mechanism that could fundamentally reshape drug development strategies.
Published in Nature, the findings challenge decades of conventional understanding about how these critical receptors function and point toward entirely new therapeutic approaches for conditions ranging from heart disease (search) to asthma (search).
"Our work shows that these receptors that essentially regulate every aspect of physiology signal using a way that we didn't appreciate before," said Sudarshan Rajagopal, MD, PhD, associate professor of medicine and senior author of the study. "That's important because it's potentially druggable; it suggests that there might be different ways to target GPCR signaling that take advantage of their use of these condensates."
A Longstanding Puzzle Solved
For decades, GPCR signaling has largely been understood as a one-to-one interaction: a receptor activates a single β-arrestin (search) protein, which then passes the signal along to the next molecule in a linear chain. Yet a persistent puzzle in the field has been how just two β-arrestin proteins manage to regulate nearly 700 different GPCRs throughout the human body.
The breakthrough emerged from an observation by MD-PhD student Preston Anderson, who noticed that at levels normally found inside cells, β-arrestins form clusters. During a beach vacation at Kure Beach, watching clouds drift and merge across the sky, Anderson began to wonder whether β-arrestins might behave similarly — assembling in a way that allowed them to communicate rather than simply clustering passively.
"When I sent it to Sudar, he basically said it wasn't going to work. But Sudar is such a great mentor; he never says no. He'll always let you do the experiment," Anderson said.
Back in the lab, Anderson attached two halves of a glowing protein to the tail ends of β-arrestins to test whether they would light up when the proteins came together. When the experiment succeeded, he recalled thinking, "We're onto something."
Multiple Lines of Evidence
Over three years, the research team validated the finding using multiple complementary approaches, including imaging to visualize β-arrestin (search) droplets both at baseline and near receptors in cells, chemical and genetic tools to promote and disrupt clustering, and functional assays demonstrating how those changes affect receptor signaling and internalization.
Together, these experiments showed that β-arrestin (search) clustering is not incidental — it directly influences how GPCRs function. When the scientists disrupted the condensates, GPCR signaling was disrupted.
"One part of our study shows that the way β-arrestins align and orient with one another influences how effectively they regulate receptor signaling," Anderson said.
Therapeutic Implications
Because condensates organize signaling in specific locations within cells, they may offer new ways to more precisely control GPCR activity. That could ultimately allow drugs to target certain signaling pathways while avoiding others — a longstanding goal in pharmacology that has proven difficult to achieve with conventional approaches.
"It's a new model for understanding how this system works," Rajagopal said. "It suggests we should start thinking about how to selectively target these condensates in the context of specific receptors."
GPCRs are found throughout the body, and drugs that act on them are used to treat conditions ranging from shock to heart disease (search) and asthma (search). Anderson noted that his interest in GPCR biology was shaped by his clinical training during the COVID-19 pandemic, when he saw patients in shock treated with the same set of GPCR-targeting drugs — such as norepinephrine and vasopressin — that have changed little in decades.
Building on a Nobel Legacy
The work builds on Duke's long legacy in GPCR research, including the discoveries of Robert Lefkowitz, MD, which helped define how these receptors function and earned the 2012 Nobel Prize in Chemistry. The new findings point to a next chapter — one in which the spatial organization of signaling becomes central to how scientists understand and target these critical systems.
Both Rajagopal and Lefkowitz are principal investigators with the Duke Cardiovascular Research Center. The study was funded by the American Heart Association, the Mandel Foundation, and the National Institutes of Health. Additional 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.