title: GHB receptor targets in the CNS: focus on high-affinity binding sites.
abstract: γ-Hydroxybutyric acid (GHB) is an endogenous compound in the mammalian brain with both low- and high-affinity receptor targets. GHB is used clinically in the treatment of symptoms of narcolepsy and alcoholism, but also illicitly abused as the recreational drug Fantasy. Major pharmacological effects of exogenous GHB are mediated by GABA subtype B (GABAB) receptors that bind GHB with low affinity. The existence of GHB high-affinity binding sites has been known for more than three decades, but the uncovering of their molecular identity has only recently begun. This has been prompted by the generation of molecular tools to selectively study high-affinity sites. These include both genetically modified GABAB knock-out mice and engineered selective GHB ligands. Recently, certain GABA subtype A (GABAA) receptor subtypes emerged as high-affinity GHB binding sites and potential physiological mediators of GHB effects. In this research update, a description of the various reported receptors for GHB is provided, including GABAB receptors, certain GABAA receptor subtypes and other reported GHB receptors. The main focus will thus be on the high-affinity binding targets for GHB and their potential functional roles in the mammalian brain.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Bay
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Eghorn
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark.
authors.forename: Anders B
authors.initials: AB
authors.lastname: Klein
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Fruebjergvej 3, 2100 Copenhagen, Denmark. Electronic address: pw@sund.ku.dk.
authors.forename: Petrine
authors.initials: P
authors.lastname: Wellendorph
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D018080:Receptors, GABA-B / Q000378:metabolism* / Q000502:physiology; D012978:Sodium Oxybate / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D012978:Sodium Oxybate
keywords: (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid; 3-hydroxycyclopent-1-enecarboxylic acid; 4-hydroxy-4-[4-(2-iodobenzyloxy)phenyl]butanoate; 4-hydroxy-4-methylpentanoic acid; 4-hydroxy-4-naphtylbutanoic acid; 5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-yl ethanoic acid; BnOPh-GHB; DS; G protein-coupled receptor; GABA; GABA subtype A; GABA subtype B; GABA(A); GABA(A) receptor; GABA(B); GABA(B) knock-out mice; GBL; GHB; GHB receptor; GPCR; HOCPCA; KO; MAPK; NCS-356; NCS-382; NCS-400; NCS-435; PERV; SSADH; SWD; T-HCA; TM; UMB68; UMB86; WT; discriminative stimulus; knock-out; mitogen-activated protein kinase; porcine endogenous retrovirus; spike-and-wave discharge; succinic semialdehyde aldehyde dehydrogenase; trans-4-hydroxycrotonic acid; transmembrane; wild-type.; γ-(p-chlorobenzyl)-γ-hydroxybutanoic acid; γ-(p-methoxybenzyl)-γ-hydroxybutanoic acid; γ-aminobutyric acid; γ-butyrolactone; γ-hydroxybutyric acid