The cloning and expression of novel G-protein coupled receptors

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

G-protein coupled receptors are proteins in the cell membrane which when activated initiate a cellular response. G-protein coupled receptors are extremely important target sites for the development of novel drugs. At least 70% of the drugs currently used in medicine are targeted at these receptors and mutations in such receptors are increasingly been recognised as important causes of specific diseases. Thus, increasing our understanding of the pharmacology and novel signalling properties of such receptors is very important, especially for the so called "orphan receptors" of this class for which the natural ligands (which 'activate' the receptor) have not yet been identified. An analysis of the genome of the model organism, Drosophila, has revealed the existence of novel genes that are structurally similar to vertebrate adrenergic receptors. Since the fruitfly does not have large amounts of the catecholamines, noradrenaline or adrenaline in its nervous system, the physiological roles of such receptors is enigmatic. We have shown that the pharmacology of the founding member of this new family of receptors is highly unusual in that it does not display a typical adrenergic receptor pharmacology and can also respond to insect steroids. One of the aims of this project is to characterize additional receptors of this class from Drosophila and related homologues (similar proteins) from a primitive vertebrate, Amphioxus, and from the human and mouse genomes, in terms of their pharmacology and mode of action. It will increase our basic knowledge of how cells in nervous systems "talk" to each other and of the way in which ?-adrenergic receptors have evolved. Another aim of this project is to identify and characterize orphan G-protein coupled receptors from the nematode worm Caenorhabditis elegans, which are involved in the control of feeding, lipid accumulation and arousal. This system is being increasing recognised as a model for a range of human disorders and diseases.