Multiple activation states of receptors
Can receptors have different active states that selectively trigger certain effects? This has long been suspected. Now there is a proof.
When a hormone or neurotransmitter activates a receptor, the simplest way to imagine this is that the receptor switches from “off” to “on.” In its active state (“on”), a receptor generates biochemical signals within the cell on whose surface it is located. These signals lead, for example, to an accelerated heartbeat or increased activity of nerve cells. However, there is a whole range of evidence to suggest that the process could be more complicated. According to this new concept, a receptor might assume different active states depending on which substance activates it. The different active states could then also trigger different reactions.
A team from Martin Lohse’s former research group at the MDC Berlin and the Collaborative Research Center 1423 in Leipzig led by Irene Coin and Andreas Bock has now provided direct evidence that receptors can have multiple active states. The results have now been published in the journal Nature.
To visualize the activation of receptors, doctoral student Romy Thomas marked their surfaces with tiny fluorescent markers. As soon as an activated receptor molecule moved, this led to an increase in fluorescence in some markers and a decrease in others. This resulted in a movement pattern of the receptor.
When the scientists activated the labeled receptors with different substances, the changes in fluorescence showed a distinct profile for each substance. In other words, each substance triggered very specific, minute movements of the receptor molecule and generated a specific active state. And each of these states in turn generated its own biochemical reactions in the cell.
These observations have important consequences for drug development, as more than a third of all drugs act via receptors. If it is now possible to generate specific activation states, then it should be possible to develop drugs that have very different effects on a specific receptor.
At ISAR Bioscience, the UniSens project, funded by the European Innovation Council, is developing an innovative method to easily measure such specific activation states of receptors. “The new evidence for different activation states of a receptor confirms the basic hypothesis of the UniSens project,” says project manager Martha Sommer. “We want to provide the pharmaceutical industry with a universally applicable detection method for these activation states to improve the development of new drugs.”
The graphic shows how a initially inactive receptor can display four characteristic movement patterns after activation by four different substances (right). The movement is visualized via a more or less intense fluorescent glow on the surface of the receptor. In this example, the intensity of the glow was measured at six distinct points on the surface of the receptor. An increase or decrease in the glow is indicated by more or less pronounced peaks and troughs at the respective measurement points. Each substance produced its own profile of peaks and troughs, i.e., specific movements in the receptor.
Thomas R, Jacoby PS, De Faveri C, Derieux C, Liebing A-D, Melkes B, Martini H-J, Bermudez M, Stäubert C, Lohse MJ, Coin I, Bock A (2026) Ligand-specific activation trajectories dictate GPCR signalling in cells, Nature (advanced online publication)
