Sensing conformational changes in metabotropic glutamate receptors

G protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and are targets of more than 25% of the medications currently on the market. Metabotropic glutamate receptors (mGluRs), family C GPCRs, modulate synaptic transmission and neuronal excitability throughout the central nervous system and thus are promising targets for the treatment of various neurological and psychiatric disorders (1). Understanding the detailed activation mechanisms of mGluRs is therefore crucial to the development of new therapeutics. Although extensively studied over the last decade, the conformational changes involved in receptor activation are still a matter of debate (2). In PNAS, Doumazane et al. (3) describe how they have developed an innovative FRET-based approach to monitor these conformational changes upon ligand binding. Their assay not only helps to resolve controversy regarding the conformational changes involved in receptor activation but also facilitates our understanding of the mode of action of allosteric modulators. This approach therefore provides a powerful tool for drug screening.