Grant: Operating Grant

Cells receive external signals--everything from light to hormones--at hundreds of different proteins or 'receptors' located on the cellular surface. Most receptors act via transducing agents known as G proteins, and such G protein-coupled receptors (GPCRs) are ubiquitous throughout biological systems. They are implicated in many diseases, and they are the targets of many drugs. Since GPCRs are so numerous, they also represent the largest pool of potential targets for new drugs and future therapeutic intervention. The critical events of G protein-mediated signalling derive from the interaction between the receptor and the G protein, and that interaction is known to be impaired in conditions such as heart disease, Alzheimer's disease and schizophrenia. The importance of this process is self-evident, yet the nature of the interaction itself and its impairment in disease remain unknown. Our investigation is aimed at an understanding of the mechanism whereby GPCRs signal to and through their attendant G proteins. Our approach is based on biophysical, biochemical and pharmacological studies of natural receptors and of mutants engineered for specific experiments. The techniques yield information on the state of the system at the molecular level. The data are interpreted in the context of mathematically formulated, mechanistic models wherein we strive to achieve a realistic description of the signalling process.