New tools for acute spatiotemporal control of GPCR signalling in vivo

The G protein coupled receptor (GPCR) family consists of approximately 800 members. They are proteins found on the surface of cells and they play important roles in virtually every process in the body. These proteins are also the target of approximately one third of all medicines used in the clinic. Unfortunately, even though these receptors have proved to be good drug targets, GPCR drug discovery is still associated with a high rate of failure, predominantly because many developed drugs do not display a sufficient therapeutic effect and/or cause unwanted side effects. This attrition is due, to a large part, to our incomplete understanding of how individual members of this receptor family control processes in the body. This is made even more complicated as many of these receptors are expressed in different cell types in different tissues. This means that a drug that acts at one of these receptors in one part of the body to have a therapeutic effect, might act at the same receptors in another part of the body to cause an adverse effect.

In order to develop better medicines, we need to understand how GPCRs in different tissues control the different processes in the body. Up until now, progress in this regard has been limited because we did not have the tools with which to selectively interrogate these processes in a cell specific manner. We aim to develop two synergistic approaches that will enable us to do this. The first approach will be to develop a strategy to restrict the action of a drug to a specific cell type by tethering it to the outside of that specific cell. The second method will allow us to switch off processes inside the cell that are initiated by GPCRs in a cell type-specific manner. We will use these methods to understand how drugs act at a GPCR that is the target of all opioid pain killers, the mu opioid receptor.

Opioids, like morphine, are the most effective drugs to treat severe pain. Unfortunately, opioids cause adverse effects such as addiction, constipation and suppression of breathing (the cause of fatality from overdose). The mu opioid receptor, a member of the GPCR family, controls both the therapeutic effects and the adverse side effects of opioid pain killers. It has been suggested opioid receptors activate two different types of proteins in nerve cells, one (G protein) that mediates pain relief, while another (arrestin) mediates adverse effects. However, recent research disputes this finding. This highlights the importance of understanding how opioid receptors activate processes in neurons that control pain relief or unwanted side effects. We propose to generate new tools that will allow us to block mu opioid receptor activation and signalling within the cell at a precise time and location in the brain. We will use this approach to understand the cell populations and cellular signalling processes that are responsible for causing the effect of opioids on breathing rate. These approaches will be widely applicable and will allow us to understand the physiological effects of a medicine when it acts at its target GPCR in an unprecedented cell specific manner with temporal precision. By understanding the role of specific cell signals in determining the therapeutic and side effects of medicines we can use this information to facilitate the discovery and development of newer safer medicines.