Orphan receptor

Orphan receptor

An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".



Examples of orphan receptors are found in the G protein-coupled receptor (GPCR)[1][2][3] and nuclear receptor[4][5][6] 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.[7] 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,[8] a type of ligand-gated ion channel. This is where the recreational drug PCP works, but no endogenous ligand is known for this site.


Historically, receptors were discovered by using ligands to "fish" for their receptors. Hence by definition, these receptors were not orphans. However with modern molecular biology techniques such as screening of cDNA libraries, it becomes possible to identify related receptors based on sequence similarity to known receptors without knowing what their ligands are.


  1. ^ Levoye A, Dam J, Ayoub MA, Guillaume JL, Jockers R (2006). "Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers". EMBO Rep 7 (11): 1094–8. doi:10.1038/sj.embor.7400838. PMC 1679777. PMID 17077864. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1679777. 
  2. ^ Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK (2006). "Orphan GPCRs and their ligands". Pharmacol Ther 110 (3): 525–32. doi:10.1016/j.pharmthera.2005.10.001. PMID 16289308. 
  3. ^ Wise A, Jupe SC, Rees S (2004). "The identification of ligands at orphan G-protein coupled receptors". Annu Rev Pharmacol Toxicol 44 (February): 43–66. doi:10.1146/annurev.pharmtox.44.101802.121419. PMID 14744238. 
  4. ^ Giguère V (October 1999). "Orphan nuclear receptors: from gene to function". Endocr. Rev. 20 (5): 689–725. doi:10.1210/er.20.5.689. PMID 10529899. 
  5. ^ Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V (2006). "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacol Rev 58 (4): 798–836. doi:10.1124/pr.58.4.10. PMID 17132856. 
  6. ^ Shi Y (June 2007). "Orphan Nuclear Receptors in Drug Discovery". Drug Discov. Today 12 (11–12): 440–5. doi:10.1016/j.drudis.2007.04.006. PMC 2748783. PMID 17532527. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2748783. 
  7. ^ Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F (April 2003). "Structural basis for bile acid binding and activation of the nuclear receptor FXR". Mol. Cell 11 (4): 1093–100. doi:10.1016/S1097-2765(03)00112-6. PMID 12718893. 
  8. ^ Fagg GE (May 1987). "Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes". Neurosci. Lett. 76 (2): 221–7. doi:10.1016/0304-3940(87)90719-1. PMID 2438606. 

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