The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is an excitatory

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

(GPCR) that binds the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

and

psychoactive drug A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

γ-hydroxybutyric acid γ-Hydroxybutyric acid, also known as ''gamma''-hydroxybutyric acid, GHB, or 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a depressant, depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brai ...

(GHB). As

solute carrier The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO ...

family 52 member 2 (SLC52A2), it is also a transporter for

riboflavin Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in ...

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. 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 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). In 2003, it was first identified in its 11-transmembrane-helix 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 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.

Function

The function of the GHB receptor appears to be quite different from that of the GABA_B receptor. It shares no

sequence homology Sequence homology is the homology (biology), biological homology between DNA sequence, DNA, RNA sequence, RNA, or Protein primary structure, protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments ...

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

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

s at higher doses, thought to be mediated through increased Na⁺/K⁺ current, and increased release of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

Ligands

Agonists

* 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA) * 4-(''p''-Chlorobenzyl)-GHB * Aceburic acid *

γ-Hydroxybutyric acid γ-Hydroxybutyric acid, also known as ''gamma''-hydroxybutyric acid, GHB, or 4-hydroxybutanoic acid, is a naturally occurring neurotransmitter and a depressant, depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brai ...

(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

Antagonists

Gabazine Gabazine (SR-95531) is a drug that acts as an antagonist at GABAA receptors. It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions if used in humans. Gabazine binds to the GABA recognition ...

(SR-95531) * NCS-382

Prodrugs

* 1,4-Butanediol - metabolised into GHB by ADH and

ALDH Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...

γ-Butyrolactone γ-Butyrolactone (GBL) or ''gamma''-butyrolactone is an organic compound with the formula . It is a hygroscopic, colorless, water-miscible liquid with a weak characteristic odor. It is the simplest Γ-lactone, 4-carbon lactone. It is mainly used ...

(GBL) – metabolised into GHB by

paraoxonase Paraoxonases are a protein family, family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates. Research ...

* γ-Valerolactone (GVL) – metabolised to GHV

Unknown/unclear

Amisulpride Amisulpride, sold under the brand names Socian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prev ...

Levosulpiride Levosulpiride, sold under the brand names Dislep and Sulpepta among others, is a dopamine antagonist medication which is used in the treatment of psychotic disorders like schizophrenia, major depressive disorder, nausea and vomiting, and gastropa ...

Prochlorperazine Prochlorperazine, formerly sold under the brand name Compazine among others, is a medication used to treat nausea, migraines, schizophrenia, psychosis and anxiety. It is a less preferred medication for anxiety. It may be taken by mouth, rectal ...

* (''R'')-4- ′-(2-Iodobenzyloxy)phenylGHB *

Sulpiride Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic) medication of the benzamide class which is used mainly in the treatment of psychosi ...

Sultopride Sultopride (trade names Barnetil, Barnotil, Topral) is an atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts a ...

References

{{GHBergics G protein-coupled receptors Gamma-Hydroxybutyric acid