Orphan receptor

Examples of orphan receptors are found in the G protein-coupled receptor (GPCR){{cite journal |vauthors=Levoye A, Dam J, Ayoub MA, Guillaume JL, Jockers R |title=Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers|journal= EMBO Rep |volume= 7 |issue= 11 |pages= 1094–8 |year= 2006| doi = 10.1038/sj.embor.7400838 |pmid= 17077864 |pmc=1679777}}{{cite journal |vauthors=Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK |title=Orphan GPCRs and their ligands|journal= Pharmacol Ther |volume= 110 |issue= 3 |pages= 525–32 |year= 2006| doi = 10.1016/j.pharmthera.2005.10.001 |pmid= 16289308}}{{cite journal |vauthors=Wise A, Jupe SC, Rees S |title=The identification of ligands at orphan G-protein coupled receptors|journal= Annu Rev Pharmacol Toxicol |volume= 44 |issue= February |pages= 43–66 |year= 2004| doi = 10.1146/annurev.pharmtox.44.101802.121419 |pmid= 14744238|s2cid=2618257 }} and nuclear receptor{{cite journal | author = Giguère V | title = Orphan nuclear receptors: from gene to function | journal = Endocr. Rev. | volume = 20 | issue = 5 | pages = 689–725 |date=October 1999 | doi = 10.1210/edrv.20.5.0378 | pmid = 10529899 | doi-access = free }}{{cite journal |author4-link=Holly Ingraham |author11-link=Ming-Jer Tsai |vauthors=Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V |title=International Union of Pharmacology. LXVI. Orphan nuclear receptors|journal= Pharmacol Rev |volume= 58 |issue= 4 |pages= 798–836 |year= 2006| doi = 10.1124/pr.58.4.10 |pmid= 17132856|s2cid=2619263 }}{{cite journal | author = Shi Y | title = Orphan Nuclear Receptors in Drug Discovery | journal = Drug Discov. Today | volume = 12 | issue = 11–12 | pages = 440–5 |date=June 2007 | pmid = 17532527 | doi = 10.1016/j.drudis.2007.04.006 | pmc = 2748783 }} families.

If an endogenous ligand is found, the orphan receptor is "adopted" or "de-orphanized".{{Cite journal|last=SHI|first=Y|title=Orphan nuclear receptors in drug discovery|journal=Drug Discovery Today|volume=12|issue=11–12|pages=440–445|doi=10.1016/j.drudis.2007.04.006|pmid=17532527|pmc=2748783|year=2007}} An example is the nuclear receptor farnesoid X receptor (FXR) and TGR5/GPCR19/G protein-coupled bile acid receptor, both of which are activated by bile acids.{{cite journal |vauthors=Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F | title = Structural basis for bile acid binding and activation of the nuclear receptor FXR | journal = Mol. Cell | volume = 11 | issue = 4 | pages = 1093–100 |date=April 2003 | pmid = 12718893 | doi = 10.1016/S1097-2765(03)00112-6| doi-access = free }} Adopted orphan receptors in the nuclear receptor group include 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,{{cite journal | author = Fagg GE | title = Phencyclidine and related drugs bind to the activated N-methyl-D-aspartate receptor-channel complex in rat brain membranes | journal = Neurosci. Lett. | volume = 76 | issue = 2 | pages = 221–7 |date=May 1987 | pmid = 2438606 | doi = 10.1016/0304-3940(87)90719-1| s2cid = 23177400 }} a type of ligand-gated ion channel. This site is where the recreational drug PCP works, but no endogenous ligand is known to bind to this site.

GPCR orphan receptors are usually given the name "GPR" followed by a number, for example GPR1. In the GPCR family, nearly 100 receptor-like genes remain orphans.{{cite journal |last1=Laschet |first1=C |last2=Dupuis |first2=N |last3=Hanson |first3=J |date=2018 |title=The G protein-coupled receptors deorphanization landscape |journal=Biochemical Pharmacology |volume=153 |pages=62–74 |doi=10.1016/j.bcp.2018.02.016 |pmid=29454621 |s2cid=3566341 }}

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 reverse pharmacology, screening of cDNA libraries, and whole genome sequencing, receptors have been identified based on sequence similarity to known receptors, without knowing what their ligands are.

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• {{cite web | url = http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=16 | title = Class A Orphans GPCRs | work = IUPHAR/BPS Guide to PHARMACOLOGY Database | publisher = University of Edinburgh / International Union of Basic and Clinical Pharmacology }}
• {{cite web | url = http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=17 | title = Adhesion Class GPCRs | work = IUPHAR/BPS Guide to PHARMACOLOGY Database | publisher = University of Edinburgh / International Union of Basic and Clinical Pharmacology }}
• {{cite web | url = http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=18 | title = Class C Orphans GPCRs | work = IUPHAR/BPS Guide to PHARMACOLOGY Database | publisher = University of Edinburgh / International Union of Basic and Clinical Pharmacology }}

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Category:Receptors