Acheiving instantaneous control of G-protein coupled receptors using light as a ligand

The discovery and development of drugs that can influence human behaviour and physiology has played a crucial role in the huge advances in medicine that have occurred over the last century. However, future progress is likely to depend in large part upon our ability to overcome some of the inherent limitations in this pharmaceutical method for treating disease. A well known problem with using drugs is that of side effects, which occur because drugs commonly have effects on multiple parts of the body. Many otherwise effective drugs are lost because of the need to minimise such adverse effects. An additional problem with drugs is that, in comparison with the natural changes in our physiology that they hope to regulate, their effects build up rather slowly and can hang around for a long time. This contributes to our tendency to become desensitised to drugs and also stops them being used in conditions in which we would like more immediate and reversible effects. For these reasons, there is a pressing need to develop new ways of adjusting our physiology that go beyond the achievements of pharmacy. We propose developing such a technology. Our approach will be to modify a group of proteins called GPCRs to make them light sensitive. GPCRs appear in practically every cell of our body. Their job is to fine tune the cell?s activity and physiology according to signals released from neighbouring cells and other parts of the body. Because they are so influential they have long been recognised as a good way of treating the symptoms of disease. Indeed more than half of currently prescribed drugs are designed to alter their activity. By making GPCRs photosensitive, we will be able to use light rather than drugs to tweak their activity. Unlike drugs, light can be switched on and off very rapidly. Light can also be applied at high doses to a single group of cells without influencing the rest of the body. These features mean that we will be able to use the new GPCRs to achieve extremely fine tuned alterations in physiology way beyond what is currently possible using drugs. In the first instance we will use this technology in animal experiments that increase our knowledge of how common medical conditions (including obesity, depression and insomnia) come about. In time, it will become a completely new way of treating medical conditions.

The development and exploitation of new technologies have underpinned numerous great advances in biomedicine. A rich source of such enabling technology has been the translation of conceptual breakthroughs in one field of research into technical innovations in another. Here we propose adopting this strategy by exploiting recent discoveries in the field of photobiology to obtain a previously unimagineable level of control over the activity of G-protein coupled receptors (GPCRs). GPCRs are a hugely influential family of proteins. They underpin intercellular communication in all major body systems by modulating second messenger systems according to the appearance of signalling molecules at the cell surface. GPCRs are therapeutic targets in a very wide variety of clinical conditions ranging from neuropsychiatric disorders to endocrine imbalances, and chronic/acute pain. Our previous work has focussed on the opsins, a branch of the GPCR family that are naturally photosensitive and provide the basis for vision. We have recently discovered that some opsins can attain photosensitivity using a cofactor (all-trans retinaldehyde) that is found throughout the body. This feature enables them to be photosensitive even when expressed outside of the retina. We propose using this information in a new strategy to achieve remote and instantaneous control of GPCR signalling. We will engineer synthetic GPCRs that comprise the light-absorbing structures of these opsins fused to the intracellular signalling components of other GPCRs. When expressed in cells of interest these photosensitised GPCRs will recapitulate native signalling upon photic stimulation. As light can be applied with very high temporal and spatial resolution this technology will allow the activity of specific GPCRs to be controlled in particular tissues (or even single cells) with microsecond resolution. Genetic control over the expression of photosensitised GPCRs will further restrict light responses to individual cell types. This unprecedented level of control will make it possible to artificially recreate natural patterns of GPCR activity for the first time. This technological advance will enable a quantum leap in cell and animal-based studies exploring the contribution of individual GPCRs to complex physiological systems, and in the development of new animal models of human disease. In the longer term, gene transfer techniques will allow this technology to be applied to clinical treatments. Given the ability of GPCRs to influence all major body systems and the inherent advantages of obtaining instantaneous control of their activity, the clinical prospects for such an approach are almost limitless.