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