ArticleProceedings of the National Academy of Sciences of the United States of America2012
α4βδ GABA(A) receptors are high-affinity targets for γ-hydroxybutyric acid (GHB).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02342366 (Multimodal Characterization of the Prosocial and Prosexual Effects of GHB Assessing Behavior, fMRI, EEG, and Neuroendocrine Mechanisms), which is not on this map. Cited by 43 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Multimodal Characterization of the Prosocial and Prosexual Effects of GHB Assessing Behavior, fMRI, EEG, and Neuroendocrine Mechanisms
Who cites it
43 citing papers in PubMed, 96 citations in OpenAlex.
- Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.Movement disorders : official journal of the Movement Disorder Society · 2023Trial
- A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity.Scientific reports · 2018Trial
- Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers.British journal of clinical pharmacology · 2015Trial
- Review
- Succinic semialdehyde dehydrogenase deficiency: a metabolic and genomic approach to diagnosis.Frontiers in genetics · 2024Article
- ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.Neurobiology of disease · 2024Article
- Synaptic effects of ethanol on striatal circuitry: therapeutic implications for dystonia.The FEBS journal · 2022Review
- Translational approaches to influence sleep and arousal.Brain research bulletin · 2022Review
- Treatment of γ-Hydroxybutyrate (GHB) Overdose with the GABAThe Journal of pharmacology and experimental therapeutics · 2022Article
- Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.International journal of molecular sciences · 2022Review
- Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse.Substance abuse and rehabilitation · 2022Review
- GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology.The AAPS journal · 2021Review
- γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion.The Journal of biological chemistry · 2020Article
- Distinct Topographical Patterns of Spike-Wave Discharge in Transgenic and Pharmacologically Induced Absence Seizure Models.Experimental neurobiology · 2019Article
- Article
- Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases.Journal of inherited metabolic disease · 2018Review
- Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: Therapeutic implications for SSADH deficiency, a GABA metabolic disorder.Toxicology in vitro : an international journal published in association with BIBRA · 2018Article
- Challenges in the development of therapeutics for narcolepsy.Progress in neurobiology · 2017Review
- A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma.Acta neuropathologica · 2017Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
γ-Hydroxybutyric acid (GHB) binding to brain-specific high-affinity sites is well-established and proposed to explain both physiological and pharmacological actions. However, the mechanistic links between these lines of data are unknown. To identify molecular targets for specific GHB high-affinity binding, we undertook photolinking studies combined with proteomic analyses and identified several GABA(A) receptor subunits as possible candidates. A subsequent functional screening of various recombinant GABA(A) receptors in Xenopus laevis oocytes using the two-electrode voltage clamp technique showed GHB to be a partial agonist at αβδ- but not αβγ-receptors, proving that the δ-subunit is essential for potency and efficacy. GHB showed preference for α4 over α(1,2,6)-subunits and preferably activated α4β1δ (EC(50) = 140 nM) over α4β(2/3)δ (EC(50) = 8.41/1.03 mM). Introduction of a mutation, α4F71L, in α4β1(δ)-receptors completely abolished GHB but not GABA function, indicating nonidentical binding sites. Radioligand binding studies using the specific GHB radioligand [(3)H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid showed a 39% reduction (P = 0.0056) in the number of binding sites in α4 KO brain tissue compared with WT controls, corroborating the direct involvement of the α4-subunit in high-affinity GHB binding. Our data link specific GHB forebrain binding sites with α4-containing GABA(A) receptors and postulate a role for extrasynaptic α4δ-containing GABA(A) receptors in GHB pharmacology and physiology. This finding will aid in elucidating the molecular mechanisms behind the proposed function of GHB as a neurotransmitter and its unique therapeutic effects in narcolepsy and alcoholism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.