Most G protein-coupled receptors (GPCRs) were found by sequence similarity. These, however, lack endogenous ligands and thus are orphan GPCRs. Although molecular biological and bioinformatics techniques made the identification of orphan GPCRs amenable, the search for their endogenous ligands has been a challenge. This search has given birth to the reverse pharmacology approach, which uses orphan GPCRs as targets to identify endogenous ligands. This approach was very successful and has led over two decades to the deorphanization of about 300 GPCRs. Many of the ligands that were matched to orphan GPCRs were already known, but a dozen is novel and in particular, nine novel neuropeptide families were discovered. These novel neuropeptides have already enriched our understanding of several important behavioural responses, in particular, the central regulation of food intake. Presently, there exist still 100 orphan GPCRs that may bind endogenous ligands that are not chemosensory.
History of the orphan GPCR research
Orphan GPCRs are receptors lacking endogenous ligands. Their history began with the discovery that the β2-adrenergic receptor and the opsins share a seven-transmembrane domain topology. These two receptors were not known to have much in common except that both couple to G proteins to elicit intracellular responses. This gave rise to the concept that all the receptors that couple to G proteins may form a supergene family, thereafter called the GPCRs. This concept gained rapid credence when metabotropic receptors for other neurotransmitters such as acetylcholine and serotonin were shown to be GPCRs. It ascertained itself when the receptor for a neuropeptide, substance K, was also found to be a GPCR.
Examples of orphan receptors are found in the G protein-coupled receptor (GPCR) and nuclear receptor families. GPCR orphan receptors are usually given the name "GPR" followed by a number, for example GPR1. If an endogenous ligand is found, the orphan receptor is "adopted". An example is the receptor FXR, which is activated by bile acids. Adopted orphan receptors in the nuclear receptor group include the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptor (PPAR). Another example of an orphan receptor site is the PCP binding site in the NMDA receptor, a type of ligand-gated ion channel. This is where the recreational drug PCP works, but no endogenous ligand is known for this site.
1. Levoye A; et al. Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers. EMBO Rep. 2006.7(11):1094-1098.