Biology:GHB receptor

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Short description: GHB receptor coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1] The rat GHB receptor was first cloned and characterised in 2003,[2] followed by the human receptor in 2007.[3]

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).[4] In 2003, it was first identified in its 11-transmembrane-helix full length, as a receptor for porcine endogenous retrovirus.[5] The same protein was later identified as the GHB receptor in 2007.[3] 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.[6]

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.[7][8][9][10][11][12]

Ligands

Agonists

Antagonists

Prodrugs

Unknown/unclear

References

  1. ↑ "Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor". Journal of Neurochemistry 75 (5): 1986–96. November 2000. doi:10.1046/j.1471-4159.2000.0751986.x. PMID 11032888. http://www.erowid.org/archive/rhodium/pdf/ghb.g-protein.receptor.evidence.pdf. 
  2. ↑ "Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB)". FASEB Journal 17 (12): 1691–3. September 2003. doi:10.1096/fj.02-0846fje. PMID 12958178. 
  3. ↑ 3.0 3.1 "Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain". FASEB Journal 21 (3): 885–95. March 2007. doi:10.1096/fj.06-6509com. PMID 17197387. 
  4. ↑ "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Letters 520 (1–3): 97–101. June 2002. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878. 
  5. ↑ "Identification of receptors for pig endogenous retrovirus". Proceedings of the National Academy of Sciences of the United States of America 100 (11): 6759–64. May 2003. doi:10.1073/pnas.1138025100. PMID 12740431. Bibcode: 2003PNAS..100.6759E. 
  6. ↑ "Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain". The Journal of Nutrition 140 (7): 1220–6. July 2010. doi:10.3945/jn.110.122911. PMID 20463145. 
  7. ↑ "Gamma-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches". Biochemical Pharmacology 58 (11): 1815–9. December 1999. doi:10.1016/S0006-2952(99)00265-8. PMID 10571257. 
  8. ↑ "[A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]" (in French). Médecine/Sciences 21 (3): 284–9. March 2005. doi:10.1051/medsci/2005213284. PMID 15745703. 
  9. ↑ "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 of Neurochemistry 87 (3): 722–32. November 2003. doi:10.1046/j.1471-4159.2003.02037.x. PMID 14535954. 
  10. ↑ "Multi-faceted aspects of gamma-hydroxybutyric acid: a neurotransmitter, therapeutic agent and drug of abuse". Mini Reviews in Medicinal Chemistry 8 (12): 1188–202. October 2008. doi:10.2174/138955708786141025. PMID 18855733. 
  11. ↑ "Unravelling the brain targets of gamma-hydroxybutyric acid". Current Opinion in Pharmacology 6 (1): 44–52. February 2006. doi:10.1016/j.coph.2005.10.001. PMID 16368267. 
  12. ↑ "Behavioral analyses of GHB: receptor mechanisms". Pharmacology & Therapeutics 121 (1): 100–14. January 2009. doi:10.1016/j.pharmthera.2008.10.003. PMID 19010351. 
  13. ↑ "Characterization and pharmacology of the GHB receptor". Annals of the New York Academy of Sciences 1139 (1): 374–85. October 2008. doi:10.1196/annals.1432.048. PMID 18991884. Bibcode: 2008NYASA1139..374T. 
  14. ↑ "α4βδ GABA(A) receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)". Proceedings of the National Academy of Sciences of the United States of America 109 (33): 13404–9. August 2012. doi:10.1073/pnas.1204376109. PMID 22753476. Bibcode: 2012PNAS..10913404A. 
  15. ↑ "1,4 Butanediol, gamma-hydroxybutyric acid and ethanol: relationships and interactions". Neuropharmacology 23 (1): 109–113. January 1984. doi:10.1016/0028-3908(84)90226-0. PMID 6717752. 
  16. ↑ "Abuse and therapeutic potential of gamma-hydroxybutyric acid". Alcohol 20 (3): 263–9. April 2000. doi:10.1016/S0741-8329(99)00090-7. PMID 10869868. 
  17. ↑ Psychopharmacology: Drugs, the Brain and Behavior. Sinauer. 2005. p. 370. ISBN 978-0-87893-534-5. 
  18. ↑ Forensic Chemistry Handbook. John Wiley & Sons. 2011-11-29. p. 386. ISBN 978-0-471-73954-8. https://books.google.com/books?id=m_vIAgAAQBAJ. 
  19. ↑ "Uptake of gamma-valerolactone--detection of gamma-hydroxyvaleric acid in human urine samples". Journal of Analytical Toxicology 37 (4): 250–4. May 2013. doi:10.1093/jat/bkt013. PMID 23486087. 
  20. ↑ "Novel high-affinity and selective biaromatic 4-substituted gamma-hydroxybutyric acid (GHB) analogues as GHB ligands: design, synthesis, and binding studies". Journal of Medicinal Chemistry 51 (24): 8088–95. December 2008. doi:10.1021/jm801112u. PMID 19053823. 



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