Rapid non-genomic actions of steroids mediated through cell surface G-protein coupled receptors
Steroids are naturally occurring substances in the body that act as sex hormones and as hormones that control the growth of tissues such as muscle and brain. Usually steroid hormones work by entering a cell and binding to special molecules called receptors. When these receptors are activated by the steroid, they can then turn on the expression in the nucleus of a range of different genes which is specific for that hormone. However, recent studies have shown that steroid hormones can also produce effects on cells rapidly, by mechanisms that do not involve them entering the cell. In these cases the steroids act with receptors on the surface of the cell which bind the hormone at their outer surface, change their shape and then pass on information about the presence of the steroid hormone to the inside of the cell. The cell then responds in an appropriate way. The protein molecules that make up one class of these cell surface receptors bind other small intercellular signalling proteins, called G-proteins, which are used to pass on messages to the rest of the cell from the receptor. Thus, these receptors are also called G-Protein Coupled Receptors or GPCRs.
We are currently studying what functions a novel cell surface GPCR from the fruitfly, Drosophila melanogaster, carries out in the animal and what processes it controls in the cells of the animal. This cell surface receptor is unusual since it can be turned on by both a class of insect steroid hormones, called the ecdysteroids, and by an adrenaline-like molecule, called dopamine. This receptor may be the insect equivalent of a highly unusual verterbate receptor called the “gamma-adrenergic receptor”. We do not yet know the structure of this vertebrate receptor but we do know that it can be activated by steroids and that the actions of these steroids can be blocked by dopamine-like molecules. Thus, the findings of our work on this Drosophila receptor will be of direct relevance to studies of this latter receptor in vertebrates, including humans, as well as to the generation of novel specific pesticides with low vertebrate toxicity.
We are also working on a number of homologous GPCRs that might be target sites for steroids from a range of other species, including the nematode worm, Caenorhabditis elegans, the protochordate Amphioxus, as well as on homologous mouse and human receptors.