Shining new light on G protein-coupled receptors by combining of a new class of sensors with tailored high-resolution fluorescence microscopy.

G protein-coupled receptors (GPCRs) are the ears and eyes of the cell. Encoded by more than 800 genes on the human genome and target for more than 30% of the marketed drugs, they sense extracellular information and translate it to intracellular action. The vast importance of these receptor molecules has resulted into a wealth of information on how they work and communicate with the cellular machinery. However, while new insights emerge on regular basis, our current understanding is still far from complete. In this project, I will unravel when and where GPCRs and their secondary messenger cAMP are active inside the living cell. I will make a novel class of sensors that generate a fluorescent signal which depends on the activation of the GPCR. In combination with existing sensors for cAMP and recently developed new types of fluorescence microscopy, I will, for the first time, see how the events of signal transduction are organized in time and space. Also, I will visualize how two such receptors, an opioid and a dopamine receptor, interact. The dynamic view on structuring of signal transduction resulting from this project will have lasting impact for basic cell biological research. In addition, given the importance of GPCRs in human health and disease, it is my strong belief that this project will benefit the medical world, leading to better and safer drugs.