GHB receptor

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.

SLC52A2
Identifiers
Aliases	SLC52A2, BVVLS2, D15Ertd747e, GPCR41, GPR172A, PAR1, RFT3, RFVT2, hRFT3, solute carrier family 52 member 2, GHB receptor, GHBh1
External IDs	OMIM: 607882; MGI: 1289288; HomoloGene: 56994; GeneCards: SLC52A2; OMA:SLC52A2 - orthologs
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8q24.3 Start 144,333,957 bp[1] End 144,361,286 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon stromal cell of endometrium right hemisphere of cerebellum granulocyte apex of heart gonad body of stomach body of pancreas spleen left adrenal cortex n/a More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding virus receptor activity riboflavin transmembrane transporter activity Cellular component integral component of membrane membrane integral component of plasma membrane plasma membrane Biological process viral entry into host cell riboflavin transport riboflavin metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 79581 52710 Ensembl ENSG00000185803 ENSG00000285112 n/a UniProt Q9HAB3 Q9D8F3 RefSeq (mRNA) NM_001253815 NM_001253816 NM_024531 NM_001363118 NM_001363120 NM_001363121 NM_001363122 NM_029643 RefSeq (protein) NP_001240744 NP_001240745 NP_078807 NP_001350047 NP_001350049 NP_001350050 NP_001350051 NP_083919 Location (UCSC) Chr 8: 144.33 – 144.36 Mb n/a PubMed search [2] [3]
Wikidata
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History

The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABA_B receptor, but also exhibit a range of effects which were found not to be produced by GABA_B 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.^[4] The rat GHB receptor was first cloned and characterised in 2003,^[5] followed by the human receptor in 2007.^[6]

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).^[7] In 2003, it was first identified in its 11-transmembrane-helix full length, as a receptor for porcine endogenous retrovirus.^[8] The same protein was later identified as the GHB receptor in 2007.^[6] 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.^[9]

Function

The function of the GHB receptor appears to be quite different from that of the GABA_B receptor. It shares no sequence homology with GABA_B, and administration of mixed GHB/GABA_B receptor agonists, along with a selective GABA_B antagonist or selective agonists for the GHB receptor which are not agonists at GABA_B, 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.^{[10][11][12][13][14][15]}

Ligands

Agonists

• 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA)
• 4-(p-Chlorobenzyl)-GHB
• Aceburic acid
• γ-Hydroxybutyric acid (GHB)
• γ-Hydroxyvaleric acid (GHV; 4-methyl-GHB)
• NCS-356 (4-(4-chlorophenyl)-4-hydroxy-but-2-enoic acid, CAS# 430440-66-7)
• NCS-435 (4-(p-methoxybenzyl)-GHB)
• trans-Hydroxycrotonic acid (T-HCA)
• UMB66
• UMB68
• UMB72
• UMB86^[16]

Antagonists

• Gabazine (SR-95531)^[17]
• NCS-382

Prodrugs

• 1,4-Butanediol - metabolised into GHB by ADH and ALDH^[18]
• γ-Butyrolactone (GBL) – metabolised into GHB by paraoxonase^[19][20][21]
• γ-Valerolactone (GVL) – metabolised to GHV^[22]

Unknown/unclear

• Amisulpride
• Levosulpiride
• Prochlorperazine
• (R)-4-[4′-(2-Iodobenzyloxy)phenyl]-GHB^[23]
• Sulpiride
• Sultopride

References

1. ENSG00000285112 GRCh38: Ensembl release 89: ENSG00000185803, ENSG00000285112 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Snead OC (November 2000). "Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor" (PDF). Journal of Neurochemistry. 75 (5): 1986–96. doi:10.1046/j.1471-4159.2000.0751986.x. PMID 11032888. S2CID 84200461.
5. Andriamampandry C, Taleb O, Viry S, Muller C, Humbert JP, Gobaille S, Aunis D, Maitre M (September 2003). "Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB)". FASEB Journal. 17 (12): 1691–3. doi:10.1096/fj.02-0846fje. PMID 12958178. S2CID 489179.
6. Andriamampandry C, Taleb O, Kemmel V, Humbert JP, Aunis D, Maitre M (March 2007). "Cloning and functional characterization of a gamma-hydroxybutyrate receptor identified in the human brain". FASEB Journal. 21 (3): 885–95. doi:10.1096/fj.06-6509com. PMID 17197387. S2CID 6069832.
7. Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S (June 2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Letters. 520 (1–3): 97–101. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878. S2CID 7116392.
8. Ericsson TA, Takeuchi Y, Templin C, Quinn G, Farhadian SF, Wood JC, et al. (May 2003). "Identification of receptors for pig endogenous retrovirus". Proceedings of the National Academy of Sciences of the United States of America. 100 (11): 6759–64. Bibcode:2003PNAS..100.6759E. doi:10.1073/pnas.1138025100. PMC 164520. PMID 12740431.
9. Yao Y, Yonezawa A, Yoshimatsu H, Masuda S, Katsura T, Inui K (July 2010). "Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain". The Journal of Nutrition. 140 (7): 1220–6. doi:10.3945/jn.110.122911. hdl:2433/174830. PMID 20463145.
10. Cash CD, Gobaille S, Kemmel V, Andriamampandry C, Maitre M (December 1999). "Gamma-hydroxybutyrate receptor function studied by the modulation of nitric oxide synthase activity in rat frontal cortex punches". Biochemical Pharmacology. 58 (11): 1815–9. doi:10.1016/S0006-2952(99)00265-8. PMID 10571257.
11. Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C (March 2005). "[A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]" [A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]. Médecine/Sciences (in French). 21 (3): 284–9. doi:10.1051/medsci/2005213284. PMID 15745703.
12. Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL (November 2003). "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. doi:10.1046/j.1471-4159.2003.02037.x. PMID 14535954. S2CID 82175813.
13. Castelli MP (October 2008). "Multi-faceted aspects of gamma-hydroxybutyric acid: a neurotransmitter, therapeutic agent and drug of abuse". Mini Reviews in Medicinal Chemistry. 8 (12): 1188–202. doi:10.2174/138955708786141025. PMID 18855733.
14. Crunelli V, Emri Z, Leresche N (February 2006). "Unravelling the brain targets of gamma-hydroxybutyric acid". Current Opinion in Pharmacology. 6 (1): 44–52. doi:10.1016/j.coph.2005.10.001. PMC 2174623. PMID 16368267.
15. Carter LP, Koek W, France CP (January 2009). "Behavioral analyses of GHB: receptor mechanisms". Pharmacology & Therapeutics. 121 (1): 100–14. doi:10.1016/j.pharmthera.2008.10.003. PMC 2631377. PMID 19010351.
16. Ticku MK, Mehta AK (October 2008). "Characterization and pharmacology of the GHB receptor". Annals of the New York Academy of Sciences. 1139 (1): 374–85. Bibcode:2008NYASA1139..374T. doi:10.1196/annals.1432.048. PMID 18991884. S2CID 37091049.
17. 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 (August 2012). "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. Bibcode:2012PNAS..10913404A. doi:10.1073/pnas.1204376109. PMC 3421209. PMID 22753476.
18. Poldrugo F, Snead OC (January 1984). "1,4 Butanediol, gamma-hydroxybutyric acid and ethanol: relationships and interactions". Neuropharmacology. 23 (1): 109–113. doi:10.1016/0028-3908(84)90226-0. PMID 6717752. S2CID 54415695.
19. Galloway GP, Frederick-Osborne SL, Seymour R, Contini SE, Smith DE (April 2000). "Abuse and therapeutic potential of gamma-hydroxybutyric acid". Alcohol. 20 (3): 263–9. doi:10.1016/S0741-8329(99)00090-7. PMID 10869868.
20. Meyer J, Quenzer LF (2005). Psychopharmacology: Drugs, the Brain and Behavior. Sinauer. p. 370. ISBN 978-0-87893-534-5.
21. Kobilinsky L (2011-11-29). Forensic Chemistry Handbook. John Wiley & Sons. p. 386. ISBN 978-0-471-73954-8.
22. Andresen-Streichert H, Jungen H, Gehl A, Müller A, Iwersen-Bergmann S (May 2013). "Uptake of gamma-valerolactone--detection of gamma-hydroxyvaleric acid in human urine samples". Journal of Analytical Toxicology. 37 (4): 250–4. doi:10.1093/jat/bkt013. PMID 23486087.
23. Høg S, Wellendorph P, Nielsen B, Frydenvang K, Dahl IF, Bräuner-Osborne H, Brehm L, Frølund B, Clausen RP (December 2008). "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. doi:10.1021/jm801112u. PMID 19053823.