The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is a 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.
|, BVVLS2, D15Ertd747e, GPCR41, GPR172A, PAR1, RFT3, RFVT2, hRFT3, solute carrier family 52 member 2, GHB receptor, GHBh1|
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. The rat GHB receptor was first cloned and characterised in 2003 followed by the human receptor in 2007.
Due to its many functions, this gene has a history of multiple discovery. 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). In 2003, it was first identified, in its 11-transmembrane-helice full length, as a receptor for porcine endogenous retrovirus. The same protein was later identified as the GHB receptor in 2007. In 2009 it was identified as a riboflavin transporter, and sorted into the 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.
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.
- 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA)
- γ-Butyrolactone (GBL)
- γ-Hydroxybutyric acid (GHB)
- γ-Hydroxyvaleric acid (GHV; 4-methyl-GHB)
- γ-Valerolactone (GVL)
- trans-Hydroxycrotonic acid (T-HCA)
- Aceburic acid
- NCS-356 (4-(4-chlorophenyl)-4-hydroxy-but-2-enoic acid, CAS# 430440-66-7)
- NCS-435 (4-(p-methoxybenzyl)-GHB)
- ENSG00000285112 GRCh38: Ensembl release 89: ENSG00000185803, ENSG00000285112 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000022560 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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.
- 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.
- 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.
- Takeda, Shigeki; Kadowaki, Shiro; Haga, Tatsuya; Takaesu, Hirotomo; Mitaku, Shigeki (5 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.
- 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 (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.
- 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" (PDF). The Journal of Nutrition. 140 (7): 1220–6. doi:10.3945/jn.110.122911. PMID 20463145.
- 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.
- 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. Archived from the original on 2009-07-15.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. doi:10.1073/pnas.1204376109. PMC 3421209. PMID 22753476.
- 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.
- A good sum-up of the multiple discoveries: gchadwick. "Are SLC52A2 and GPR172A really the same?". Biology Stack Exchange.