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Researchers from the Collaborative Research Centre (CRC) 1423 have, for the first time, investigated directly in living cells how a key membrane receptor – which, among other functions, helps regulate heart activity – interacts with its signalling partners. Depending on the drug applied, this receptor adopts different conformations and operates at different speeds, which in turn influences which signals are passed on within the cell.
The novel biosensor technology used in this study can also be transferred to other so-called G protein-coupled receptors (GPCRs), which act as crucial “signal receivers” in our cells and are of major medical relevance. According to the study leaders, Professor Irene Coin and Professor Andreas Bock, these new findings – just published in the prestigious journal Nature – open up new possibilities for the targeted development of medicines that trigger only the desired signalling pathways.
“We expect similar activation processes to occur in many other receptors as well. Our biosensors could help identify compounds that act precisely on specific signalling pathways within the cell or that preferentially activate particular G proteins,” explains Professor Irene Coin from the Institute of Biochemistry at Leipzig University. For a long time, receptors were thought to function like simple on–off switches within cells. Laboratory experiments have since shown, however, that these receptors do not exist in a single state but can switch between multiple inactive and active conformations. These insights were gained from studies of isolated receptors embedded in artificial cell membranes, where extremely small measurement probes could be used that scarcely altered the receptor itself.
Observing receptor movements in real time
In living cells, however, this is far more challenging. Researchers typically rely on fluorescent proteins, which are considerably larger and therefore unable to capture subtle conformational changes in receptors with sufficient precision. As a result, it had previously been unclear whether these receptors can also adopt multiple distinct active states in real, living cells. “We have developed a new type of biosensor in which tiny fluorescent molecules are attached directly to the receptors in living cells,” says Professor Irene Coin. She is one of the pioneers in incorporating specialised artificial building blocks – referred to as unnatural amino acids – directly into proteins.
Using this method, known as genetic code expansion, the researchers were able to selectively modify specific sites on the M2 receptor and insert an artificial amino acid called TCOK. Fluorescent molecules were then attached to these TCOK sites via a chemical reaction. This produced sensors whose fluorescence changes as soon as the receptor becomes active, enabling the scientists to observe the movements of specific receptor segments in real time. In addition, the team employed a range of well-established techniques to verify that the sensors functioned reliably and that the effects of the different compounds were measured accurately.
Major success for Collaborative Research Centre (CRC) 1423
“This publication represents a major success for a project within Collaborative Research Centre (CRC) 1423 – Structural Dynamics of GPCR Activation and Signaling – which is based at our university, and also reflects the excellence of its research,” emphasises the biochemist. The CRC is housed within the Faculty of Life Sciences at Leipzig University. The project was conceived and led by Professor Irene Coin and Professor Andreas Bock and emerged from close collaboration between their two research groups.
Leipzig has a long-standing tradition of research focused on understanding how molecules and cells in our bodies communicate with one another. This communication is largely mediated by membrane receptors – proteins embedded in the cell surface that transmit signals from outside the cell to its interior. The largest class of these receptors are G protein-coupled receptors (GPCRs). Around one third of all medicines currently on the market act on such receptors. To develop more effective drugs with fewer side effects, it is essential to understand how these receptors are activated and how signal transmission takes place. Two factors are crucial in this context: first, how the different parts of a receptor move when a compound binds to it; and second, the timing of these movements.
“We have already established biosensors for additional GPCRs in our laboratories and are pursuing further research questions. At the same time, we are working to push the methodology to its limits,” says Professor Irene Coin. “There is no doubt that this project will be included in the third funding phase of CRC 1423.”
Prof. Dr. Irene Coin
Institut für Biochemie
Telefon: +49 341 97-36996
irene.coin@uni-leipzig.de
https://www.nature.com/articles/s41586-025-09963-3
Ligand-specific activation trajectories dictate GPCR signalling in cells, DOI: 10.1038/s41586-025-09963-3
https://research.uni-leipzig.de/sfb1423/
Professor Irene Coin and Professor Andreas Bock
Source: Christian Hüller/Private
Copyright: Leipzig University
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