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A research team of the University Medical Center Mainz has succeeded in observing for the first time how in living cells, G protein-coupled receptors actually respond to activating substances. The scientists discovered that, depending on the activating substance bound, one and the same receptor takes on different forms and thus triggers different cell reactions. In the long term, these outstanding new findings in basic research could contribute to the development of new drugs that target specific receptors, thereby acting more precisely and also having fewer side effects. The results have been published in the current issue of the renowned journal Nature.
Many vital physiological processes, such as heart function and the immune system, are influenced by so-called G protein coupled receptors (GPCRs). These are located on the cell surface, where they receive and recognize signals from their environment. They transmit these stimuli to the cell interior by activating so-called G proteins. These in turn trigger specific cellular responses, such as a faster heartbeat or an immune response. Due to these so-called signaling cascades, GPCRs are the most important target structure for about one-third of all licensed drugs.
Investigating these important cell receptors is highly relevant because it helps to better understand what causes diseases and why drugs have certain beneficial effects and unwanted side effects. Studies on isolated GPCRs in the “test tube” have already yielded fundamental insights into how these cell receptors function. However, it has not yet been possible to clarify in comparable detail how the receptors behave in living cells.
Molecular spies reveal ‘movements’ of cell receptors
Now, Professor and Chair of Pharmacology Andreas Bock, PhD, Director of the Institute of Pharmacology at the University Medical Center Mainz, has shed light on the matter – with glowing cell receptors. In cooperation with Prof. Dr. Irene Coin from Leipzig University and funded by the DFG's Collaborative Research Centre 1423 “Structural Dynamics of GPCR Activation and Signaling,” Andreas Bock and his team developed so-called biosensors that make it possible, for the first time, to directly track in living cells how a receptor moves in the native cell membrane and changes its structure after it has bound to a drug and is coupled to a G protein. In order to observe the receptors in real time, the researchers genetically modified them in advance so that they could connect the receptors to so-called fluorophores. These are small molecules that glow when illuminated. It is this fluorescence that makes the cell receptors visible in the first place. That is why such biosensors are also called “molecular spies.”
Light signals as unique as a fingerprint
The fluorescence patterns produced by the glowing biosensors depend on which activating substance (e.g. a drug) and which G protein bind to the receptor. Surprisingly, the patterns are as individual as a fingerprint and can therefore be assigned to different receptor forms. The results thus provide a molecular explanation for a long-known but poorly understood phenomenon: Why can different drugs that bind to the same receptor have different effects?
Receptor function in living cells is preserved
What is special about these biosensors is that they barely interfere with the function of the cell receptors. “This is because we have genetically modified the receptors only minimally at a single point,” explains Professor Bock. “At this positions, the fluorophores – which are much smaller than the receptors – bind. This is important in order to avoid interference with their response to received signals.”
Previous methods relied on fluorescent proteins that were almost as large as the cell receptors themselves, making it impossible for the cell receptors to function naturally. Only the newly developed biosensors from Professor Bock's research group provide novel insight into receptor activation in living cells. They reveal which activating substances trigger which receptor movements in which order and how this affects the cell response. In the long term, this new technology could increase the chances of developing customized drugs with few side effects.
Original publication:
Romy Thomas, Pauline S. Jacoby, Chiara De Faveri, Cécile Derieux, Aenne-Dorothea Liebing, Barbora Melkes, Hans-Joachim Martini, Marcel Bermudez, Claudia Stäubert, Martin J. Lohse, Irene Coin, Andreas Bock.
Ligand-specific activation trajectories dictate GPCR signalling in cells, Nature (2026)
DOI: https://doi.org/10.1038/s41586-025-09963-3
Contact:
Univ.-Prof. Dr. Andreas Bock
Director of the Institute of Pharmacology
University Medical Center Mainz
andreas.bock@uni-mainz.de
Press contact:
Nadine Berger M. Sc.
Corporate Communications
University Medical Center Mainz
phone +49 (0)6131 17-8434
pr@unimedizin-mainz.de
About the University Medical Center of the Johannes Gutenberg University Mainz
The University Medical Center of the Johannes Gutenberg University Mainz is the only medical institution of supra-maximum supply in the German state of Rhineland-Palatinate and an internationally recognized science location. Medical and scientific specialists at more than 60 clinics, institutes and departments work interdisciplinarily to treat around 403,000 patients per year. Highly specialized patient care, research and teaching are inseparably intertwined. Around 3,700 medicine and dentistry students as well as around 590 future medical, commercial and technical professionals are trained in Mainz. With a workforce of approximately 9,000 colleagues the University Medical Center Mainz is one of the largest employers in the region and an important driver of growth and innovation. Find more information online at https://www.unimedizin-mainz.de
Univ.-Prof. Dr. Andreas Bock
Director of the Institute of Pharmacology
University Medical Center Mainz
andreas.bock@uni-mainz.de
Romy Thomas, Pauline S. Jacoby, Chiara De Faveri, Cécile Derieux, Aenne-Dorothea Liebing, Barbora Melkes, Hans-Joachim Martini, Marcel Bermudez, Claudia Stäubert, Martin J. Lohse, Irene Coin, Andreas Bock.
Ligand-specific activation trajectories dictate GPCR signalling in cells, Nature (2026)
DOI: https://doi.org/10.1038/s41586-025-09963-3
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