Orphan G Protein-coupled Receptors in Post-Genome Era

In 'Nature', Dixon et al. reported the first cloned mammalian G-protein coupled receptor sequence (1). The DNA sequence from a hamster encodes the |32-aderenergic receptor. In the same year, 1986, Kubo et al. published the muscarinic acetylcholine receptor sequence (Ml) from a rat in the same journal (2). Both groups purified the receptor proteins and identified the DNA sequences (1,2). These novel findings opened a new era of pharmacology, a period I would call the 'receptor-hunting period'. Lots of G-protein coupled receptors (GPCR) for known ligands like histamine, serotonin, prostaglandin and even morphine have been cloned by PCR (polymerase chain reaction), low stringency hybridization, and expression cloning techniques (3). Now, the Human Genome Project is completed and all the candidate genes are available to be studied (4,5). Almost 350 GPCRs are considered as functional receptors in human beings excluding olfactory receptors (6). Among the genes, about 200 GPCRs are matched with their own ligands. However, the rest of the GPCRs are classified as 'orphan receptors', because their natural ligands are not yet known (6). Considering that half or more than half of the drugs on the current market are acting on the GPCRs positively (agonists) or negatively (antagonists), the orphan receptor project is a fascinating 'goldmine* to the pharmaceutical companies and academia scientists. In my speech, I'd like to introduce the techniques useful for the orphan receptor research with several successful examples and prospect the future of the orphan receptor research.