Orphan G-protein-coupled receptors and natural ligand discovery

The superfamily of seven-transmembrane-domain G-protein-coupled receptors ( GPCRs) is the largest and most diverse group of transmembrane proteins invo lved in signal transduction, Each of the similar to 1000 family members fou nd in vertebrates responds to stimuli as diverse as hormones, neurotransmit ters, odorants and light, which selectively activate intracellular signalin g events mediated by heterotrimeric G proteins. Because GPCRs are centrally positioned in the plasma membrane to initiate a cascade of cellular respon ses by diverse extracellular mediators, it is not surprising that modulatio n of GPCR function has been successful in the development of many marketed therapeutic agents. It has become clear that GPCRs far which a natural acti vating ligand has not yet been identified (orphan GPCRs) might provide a pa th to discovering new cellular substances that are important in human physi ology The process of'de-orphanizing' these novel proteins has accelerated s ignificantly and opened up new avenues for research in human physiology and pharmacology.