Orphan G protein-coupled receptors: Targets for new therapeutic interventions

With the completion of the human genome, many genes will be uncovered with unknown functions. The 'orphan' G protein coupled receptors (GPCRs) are examples of genes without known functions. These are genes that exhibit the seven helical conformation hallmark of the GPCRs but that are called 'orphans' because they are activated by none of the primary messengers known to activate GPCRs in vivo. They are the targets of undiscovered transmitters and this lack of knowledge precludes understanding their function. Yet, because they belong to the supergene family that has the widest regulatory role in the organism, the orphan GPCRs have generated much excitement in academia and industry. They hold much hope for revealing new intercellular interactions that will open new areas of basic research which ultimately will lead to new therapeutic applications. However, the first step in understanding the function of orphan GPCRs is to 'deorphanize' them, to identify their natural transmitters. Here we review the search for the natural primary messengers of orphan GPCRs and focus on two recently deorphanized GPCR systems, the melanin-concentrating hormone (MCH) and prolactin-releasing peptide (PrRP) systems, to illustrate the strategies applied to solve their function and to exemplify the therapeutic potentials that such systems hold.