Reassessing how cells respond to drugs
G protein-coupled receptors (GPCRs), which sit in cell membranes and relay signals from the outside to the inside of cells, are often described as simple switches: When a molecule, such as a neurotransmitter or hormone, binds to them, it sets off a domino-like chain reaction, a so-called signaling cascade, inside cells to elicit a specific cellular function.
Now a study published in “Nature” by Dr. Romy Thomas, a former graduate student in the Receptor Signaling lab at the Max Delbrück Center and now a postdoc at Stanford University, and collaborators at the University Medical Center of the Johannes Gutenberg-University Mainz and Leipzig University, suggests a more complex mechanism. The researchers demonstrate that GPCRs can follow multiple activation pathways in cells – with different molecules driving the same receptor to distinct active states which may favor certain signaling pathways over others.
“We found that GPCRs do not behave like simple on-off switches,” explains senior author Professor Andreas Bock, former interim Co-Group Leader of the Receptor Signaling lab and now Director of the Institute of Pharmacology at the University Medical Center Mainz. “Instead, depending on the molecule that binds to them, they take on different shapes, with each conformation determining a specific signaling outcome.”
The Receptor Signaling lab was founded by Professor Martin Lohse, an author of the paper who mentored Bock in his lab. Lohse is also a former Scientific Director of the Max Delbrück Center and is now Chairman of ISAR Bioscience.
Probing receptor motion in living cells
Previous studies have suggested that GPCRs can switch between multiple inactive and active conformations. But these insights were gained from studies of isolated receptors embedded in artificial cell membranes. Studying such changes in living cells has been more challenging because existing techniques have been unable to capture subtle conformational changes in receptors with sufficient precision.
The cell membranes of human kidney cells are marked with fluorescent biomarkers to track how G protein coupled receptors change activity when bound to molecules such as neurotransmitters or hormones.
Using the M2 muscarinic acetylcholine receptor as a model, the team attached tiny fluorescent probes to precise positions on the receptor in living cells. The technology to attach the probes to the cells was developed by Professor Irene Coin from the Institute of Biochemistry at Leipzig University. When the scientists activated the fluorescently labeled receptors with different substances, each caused distinct changes in fluorescence. In other words, each substance triggered very specific, minute movements of the receptor molecule to create a unique active state. And each of these states in turn generated its own set of biochemical reactions in the cell.
Bock credits Lohse for connecting he and Coin. “It was Lohse who suggested that I meet Irene and collaborate with her on something bigger,” says Bock. He remained available to us as one of the most important persons with whom to discuss our research, which took years, and he helped to shape the concept.”
Designing better drugs
GPCRs control processes such as heart rate, signaling in the brain, and hormone responses – and more than a third of all approved drugs act on them. “Our study may help explain why drugs targeting the same receptor can have very different effects,” says Thomas. “They are not just turning the receptor on – they are steering it along unique pathways.”
“We expect similar activation processes to occur in many other receptors as well,” adds Coin. “Our biosensors could help identify compounds that act precisely on specific signaling pathways within the cell, or that preferentially activate particular proteins.”
When developing drugs, instead of asking whether a drug merely activates a receptor, researchers can now investigate how it changes a receptor, and what kind of signaling it triggers inside cells. Such information may help scientists better design drugs to guide receptors along specific activation paths, and develop medications that are more precise and cause fewer side effects.
Text: Gunjan Sinha and Leipzig University
This research was supported by the Collaborative Research Centre (CRC) 1423 – Structural Dynamics of GPCR Activation and Signaling based at Leipzig University. It began in 2019 as a collaborative project with the Max Delbrück Center and Charité – Universitätsmedizin Berlin.
Further information
Literature
Romy Thomas, Pauline Jacoby, Chiara De Faveri, et. al. (2026) “Ligand-specific activation trajectories dictate GPCR signaling in cells,” Nature. DOI: 10.1038/s41586-025-09963-3
Contacts
Nadine Berger M. Sc.
Corporate Communications
University Medical Center Mainz
+49 (0)6131 17-8434
Nadine.Berger@unimedizin-mainz.de
Nina Vogt
Media Team
Leipzig University
Communications
+ 49 341 97-35026
presse@uni-leipzig.de
Gunjan Sinha
Editor, Communications
Max Delbrück Center
+49 30 9406-2118
Gunjan.Sinha@mdc-berlin.de or presse@mdc-berlin.de
Prof. Dr. Andreas Bock
Director of the Institute of Pharmacology
University Medical Center Mainz
andreas.bock@uni-mainz.de
- Max Delbrück Center
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association lays the foundation for the medicine of tomorrow through our discoveries of today. At locations in Berlin-Buch, Berlin-Mitte, Heidelberg, and Mannheim, interdisciplinary teams investigate the complexity of disease at the systems level – from molecules and cells to organs and entire organisms. Together with academic, clinical, and industry partners, and as part of global networks, we turn biological insights into innovations for early detection, personalized therapies, and disease prevention. Founded in 1992, the Max Delbrück Center is home to a vibrant, international research community of around 1,800 people from over 70 countries. We are 90 percent funded by the German federal government and 10 percent by the state of Berlin.
