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GHB receptor

{{Short description|GHB receptor coding gene in the species Homo sapiens}}

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The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is an excitatory G protein-coupled receptor (GPCR) that binds the neurotransmitter and psychoactive drug γ-hydroxybutyric acid (GHB). As solute carrier family 52 member 2 (SLC52A2), it is also a transporter for riboflavin.

History

The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted.{{cite journal | vauthors = Snead OC | title = Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor | journal = Journal of Neurochemistry | volume = 75 | issue = 5 | pages = 1986–96 | date = November 2000 | pmid = 11032888 | doi = 10.1046/j.1471-4159.2000.0751986.x | s2cid = 84200461 | url = http://www.erowid.org/archive/rhodium/pdf/ghb.g-protein.receptor.evidence.pdf | doi-access = free }} The rat GHB receptor was first cloned and characterised in 2003,{{cite journal | vauthors = Andriamampandry C, Taleb O, Viry S, Muller C, Humbert JP, Gobaille S, Aunis D, Maitre M | s2cid = 489179 | title = Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB) | journal = FASEB Journal | volume = 17 | issue = 12 | pages = 1691–3 | date = September 2003 | pmid = 12958178 | doi = 10.1096/fj.02-0846fje | doi-access = free }} followed by the human receptor in 2007.{{cite journal | vauthors = Andriamampandry C, Taleb O, Kemmel V, Humbert JP, Aunis D, Maitre M | s2cid = 6069832 | title = Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain | journal = FASEB Journal | volume = 21 | issue = 3 | pages = 885–95 | date = March 2007 | pmid = 17197387 | doi = 10.1096/fj.06-6509com | doi-access = free }}

Due to its many functions, this gene has a history of multiple discoveries. In 2002, data mining in the human genome found an incorrectly spliced form of this protein with eight transmembrane helices, and due to the presence of a G-protein binding site, it was correctly assumed to be a GPCR (as GCPR41).{{cite journal | vauthors = Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S | title = Identification of G protein-coupled receptor genes from the human genome sequence | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 97–101 | date = June 2002 | pmid = 12044878 | doi = 10.1016/S0014-5793(02)02775-8 | s2cid = 7116392 | doi-access = free }} In 2003, it was first identified in its 11-transmembrane-helix full length, as a receptor for porcine endogenous retrovirus.{{cite journal | vauthors = Ericsson TA, Takeuchi Y, Templin C, Quinn G, Farhadian SF, Wood JC, Oldmixon BA, Suling KM, Ishii JK, Kitagawa Y, Miyazawa T, Salomon DR, Weiss RA, Patience C | display-authors = 6 | title = Identification of receptors for pig endogenous retrovirus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 11 | pages = 6759–64 | date = May 2003 | pmid = 12740431 | pmc = 164520 | doi = 10.1073/pnas.1138025100 | bibcode = 2003PNAS..100.6759E | doi-access = free }} The same protein was later identified as the GHB receptor in 2007. In 2009, it was identified as a riboflavin transporter, and sorted into SLC family 52 due to sequence similarity. The authors of the 2009 study were not aware of the 2007 study showing that it actually does function as a GPCR.{{cite journal | vauthors = Yao Y, Yonezawa A, Yoshimatsu H, Masuda S, Katsura T, Inui K | title = Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain | journal = The Journal of Nutrition | volume = 140 | issue = 7 | pages = 1220–6 | date = July 2010 | pmid = 20463145 | doi = 10.3945/jn.110.122911 | doi-access = free | hdl = 2433/174830 | hdl-access = free }}

Function

The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists, along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect, followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current, and increased release of dopamine and glutamate.{{cite journal | vauthors = Cash CD, Gobaille S, Kemmel V, Andriamampandry C, Maitre M | title = Gamma-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches | journal = Biochemical Pharmacology | volume = 58 | issue = 11 | pages = 1815–9 | date = December 1999 | pmid = 10571257 | doi = 10.1016/S0006-2952(99)00265-8 }}{{cite journal | vauthors = Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C | title = [A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse] | language = French | journal = Médecine/Sciences | volume = 21 | issue = 3 | pages = 284–9 | date = March 2005 | pmid = 15745703 | doi = 10.1051/medsci/2005213284 | trans-title = A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse | doi-access = free }}{{cite journal | vauthors = Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL | title = Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid | journal = Journal of Neurochemistry | volume = 87 | issue = 3 | pages = 722–32 | date = November 2003 | pmid = 14535954 | doi = 10.1046/j.1471-4159.2003.02037.x | s2cid = 82175813 }}{{cite journal | vauthors = Castelli MP | title = Multi-faceted aspects of gamma-hydroxybutyric acid: a neurotransmitter, therapeutic agent and drug of abuse | journal = Mini Reviews in Medicinal Chemistry | volume = 8 | issue = 12 | pages = 1188–202 | date = October 2008 | pmid = 18855733 | doi = 10.2174/138955708786141025 }}{{cite journal | vauthors = Crunelli V, Emri Z, Leresche N | title = Unravelling the brain targets of gamma-hydroxybutyric acid | journal = Current Opinion in Pharmacology | volume = 6 | issue = 1 | pages = 44–52 | date = February 2006 | pmid = 16368267 | pmc = 2174623 | doi = 10.1016/j.coph.2005.10.001 }}{{cite journal | vauthors = Carter LP, Koek W, France CP | title = Behavioral analyses of GHB: receptor mechanisms | journal = Pharmacology & Therapeutics | volume = 121 | issue = 1 | pages = 100–14 | date = January 2009 | pmid = 19010351 | pmc = 2631377 | doi = 10.1016/j.pharmthera.2008.10.003 }}

Ligands

=Agonists=

=Antagonists=

  • Gabazine (SR-95531){{cite journal | vauthors = Absalom N, Eghorn LF, Villumsen IS, Karim N, Bay T, Olsen JV, Knudsen GM, Bräuner-Osborne H, Frølund B, Clausen RP, Chebib M, Wellendorph P | title = α4βδ GABA(A) receptors are high-affinity targets for γ-hydroxybutyric acid (GHB) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 33 | pages = 13404–9 | date = August 2012 | pmid = 22753476 | pmc = 3421209 | doi = 10.1073/pnas.1204376109 | bibcode = 2012PNAS..10913404A | doi-access = free }}
  • NCS-382

= Prodrugs =

  • 1,4-Butanediol - metabolised into GHB by ADH and ALDH{{cite journal | vauthors = Poldrugo F, Snead OC | title = 1,4 Butanediol, gamma-hydroxybutyric acid and ethanol: relationships and interactions | journal = Neuropharmacology | volume = 23 | issue = 1 | pages = 109–113 | date = January 1984 | pmid = 6717752 | doi = 10.1016/0028-3908(84)90226-0 | s2cid = 54415695 }}
  • γ-Butyrolactone (GBL) – metabolised into GHB by paraoxonase{{cite journal | vauthors = Galloway GP, Frederick-Osborne SL, Seymour R, Contini SE, Smith DE | title = Abuse and therapeutic potential of gamma-hydroxybutyric acid | journal = Alcohol | volume = 20 | issue = 3 | pages = 263–9 | date = April 2000 | pmid = 10869868 | doi = 10.1016/S0741-8329(99)00090-7 }}{{cite book| vauthors = Meyer J, Quenzer LF |title=Psychopharmacology: Drugs, the Brain and Behavior|title-link=Psychopharmacology|publisher=Sinauer|year=2005|isbn=978-0-87893-534-5|page=370}}{{cite book| vauthors = Kobilinsky L |url=https://books.google.com/books?id=m_vIAgAAQBAJ|title=Forensic Chemistry Handbook| date=2011-11-29 |isbn=978-0-471-73954-8 |page=386 | publisher=John Wiley & Sons }}
  • γ-Valerolactone (GVL) – metabolised to GHV{{cite journal | vauthors = Andresen-Streichert H, Jungen H, Gehl A, Müller A, Iwersen-Bergmann S | title = Uptake of gamma-valerolactone--detection of gamma-hydroxyvaleric acid in human urine samples | journal = Journal of Analytical Toxicology | volume = 37 | issue = 4 | pages = 250–4 | date = May 2013 | pmid = 23486087 | doi = 10.1093/jat/bkt013 | doi-access = free }}

=Unknown/unclear=

  • Amisulpride
  • Levosulpiride
  • Prochlorperazine
  • (R)-4-[4′-(2-Iodobenzyloxy)phenyl]-GHB{{cite journal | vauthors = Høg S, Wellendorph P, Nielsen B, Frydenvang K, Dahl IF, Bräuner-Osborne H, Brehm L, Frølund B, Clausen RP | title = Novel high-affinity and selective biaromatic 4-substituted gamma-hydroxybutyric acid (GHB) analogues as GHB ligands: design, synthesis, and binding studies | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 24 | pages = 8088–95 | date = December 2008 | pmid = 19053823 | doi = 10.1021/jm801112u }}
  • Sulpiride
  • Sultopride

References

{{Reflist}}

{{G protein-coupled receptors}}

{{GHBergics}}

Category:G protein-coupled receptors

Category:Gamma-Hydroxybutyric acid