Grant: Project Grant

A family of approx. 800 different G-protein-coupled receptors (GPCRs) in our cell membranes controls most of our physiology by sensing hormones, neurotransmitters and chemical signals, which result in the modulation of signaling pathways. More than a third of current prescription drugs target GPCRs. The adenosine A2A receptor is a prototypical GPCR and an important drug target for a wide spectrum of diseases including oncologic, inflammatory, Parkinson's and cardiovascular diseases. GPCRs can adopt different shapes (conformations), of which only active conformations couple to G proteins and modulate intracellular signaling. Detailed molecular insight into receptor shape changes and G protein coupling will provide new avenues for pharmaceutical intervention. How G proteins are activated by adenosine A2A receptors and modulate intracellular signaling can be uncovered with paramagnetic resonance techniques like EPR and DEER spectroscopy, where small labels are covalently attached to the individual proteins which allow us to "visualize" GPCR conformations. The effect of pharmaceuticals on the A2A receptor and its subsequent interaction with intra-cellular binding partners, like G proteins, can be interrogated using the labels as environmentally sensitive antennas. Measuring distances between two labels attached to a protein allows the "visualization" of conformational changes. Our research centre is the sole facility in Canada for these vital and complex spectroscopic techniques, allowing us to monitor the responses of pharmaceutical compounds on the dynamic interplay between A2A receptor and G proteins. We wish to enhance our understanding of A2A receptor-mediated G protein activation to improve our still limited knowledge about this crucial drug target and GPCRs in general.