G protein-coupled receptors (GPCRs) are the largest family of cell surface signal transducing proteins encoded by the human genome. They allow the cell to respond to diverse array of extracellular signals, control most (patho)physiological processes, and are currently the therapeutic target of over 30% of marketed drugs. However, GPCR drug discovery is still characterised by a very high attrition rate, which reflects our inadequate understanding of the complex mechanisms of GPCR signalling and regulation.Up until recently, understanding of GPCR function was obtained from snapshots of receptors at different points in time and a major limitation for the study of GPCRs has been the inability to assess receptor activation and subsequent signalling events with high temporal (duration and frequency) or spatial (location) resolution. However, in the recent years there has been an explosion of biophysical and imaging approaches that will allow greater temporal and spatial resolution of receptor function than ever before. In this project we will measure ligand binding, receptor conformational changes, G protein activation, recruitment of regulatory proteins and receptor trafficking in real time and in live cells. We will therefore obtain detailed mechanistic understanding of the dynamics of GPCR activity in health and in disease that will reveal novel intervention points for future, more effective receptor-based therapies.This proposal combines my expertise in the study of GPCR interacting proteins and their role in receptor signalling and trafficking with the expertise of the Host Institution in the application of state-of-the-art imaging and biophysical approaches to study of this receptor family. As such, this project will not only broaden my research and technical skills in GPCR visualization, but it will also result in the establishment of a unique technological platform for the study of the dynamics of GPCR function within the Host Institution.