Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors.
paper
Cited
Public
Unavailable
- Authors
- Hanchar, H Jacob; Chutsrinopkun, Panida; Meera, Pratap; Supavilai, Porntip; Sieghart, Werner; Wallner, Martin; Olsen, Richard W
- Year
- 2006
- Journal
- Proceedings of the National Academy of Sciences of the United States of America
- PMID
- 16581914
- DOI
- 10.1073/pnas.0509903103
- PMCID
- PMC1482528
Although GABA(A) receptors have long been implicated in mediating ethanol (EtOH) actions, receptors containing the "nonsynaptic" delta subunit only recently have been shown to be uniquely sensitive to EtOH. Here, we show that delta subunit-containing receptors bind the imidazo-benzodiazepines (BZs) flumazenil and Ro15-4513 with high affinity (K(d) < 10 nM), contrary to the widely held belief that these receptors are insensitive to BZs. In immunopurified native cerebellar and recombinant delta subunit-containing receptors, binding of the alcohol antagonist [(3)H]Ro15-4513 is inhibited by low concentrations of EtOH (K(i) approximately 8 mM). Also, Ro15-4513 binding is inhibited by BZ-site ligands that have been shown to reverse the behavioral alcohol antagonism of Ro15-4513 (i.e., flumazenil, beta-carbolinecarboxylate ethyl ester (beta-CCE), and N-methyl-beta-carboline-3-carboxamide (FG7142), but not including any classical BZ agonists like diazepam). Experiments that were designed to distinguish between a competitive and allosteric mechanism suggest that EtOH and Ro15-4513 occupy a mutually exclusive binding site. The fact that only Ro15-4513, but not flumazenil, can inhibit the EtOH effect, and that Ro15-4513 differs from flumazenil by only a single group in the molecule (an azido group at the C7 position of the BZ ring) suggest that this azido group in Ro15-4513 might be the area that overlaps with the alcohol-binding site. Our findings, combined with previous observations that Ro15-4513 is a behavioral alcohol antagonist, suggest that many of the behavioral effects of EtOH at relevant physiological concentrations are mediated by EtOH/Ro15-4513-sensitive GABA(A) receptors.
No figures extracted from this document.
No chunks β full text not yet ingested.
No entities extracted from this document yet.
No uploaded files.
Not in any collection.
No citations found.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| GABA system as the cause and effect in early development. | Topchiy I et al. | β | 2024 | β |
| The TMEM132B-GABA<sub>A</sub> receptor complex controls alcohol actions in the brain. | Wang G et al. | β | 2024 | β |
| Cerebellar Ξ±6GABA<sub>A</sub> Receptors as a Therapeutic Target for Essential Tremor: Proof-of-Concept Study with Ethanol and Pyrazoloquinolinones. | Huang YH et al. | β | 2023 | β |
| Differential assembly diversifies GABA<sub>A</sub> receptor structures and signalling. | Sente A et al. | β | 2022 | β |
| <i>Ξ±</i>6-Containing GABA<sub>A</sub> Receptors: Functional Roles and Therapeutic Potentials. | Sieghart W et al. | β | 2022 | β |
| Sex differences in the alcohol-mediated modulation of BLA network states | DiLeo A et al. | β | 2022 | β |
| Sex Differences in the Alcohol-Mediated Modulation of BLA Network States. | DiLeo A et al. | β | 2022 | β |
| Delta-containing GABA<sub>A</sub> receptors in pain management: Promising targets for novel analgesics. | Luo Y et al. | β | 2021 | β |
| Direct Structural Insights into GABA<sub>A</sub> Receptor Pharmacology. | Kim JJ et al. | β | 2021 | β |
| Differential sensitivity of human neurons carrying ΞΌ opioid receptor (MOR) N40D variants in response to ethanol. | Scarnati MS et al. | β | 2020 | β |
| Do Toxic Synergies of Underlying Etiologies Predispose the Positive Association Between Traumatic Brain Injury and ADHD? | Fluegge K | β | 2020 | β |
| Humulone Modulation of GABA<sub>A</sub> Receptors and Its Role in Hops Sleep-Promoting Activity. | Benkherouf AY et al. | β | 2020 | β |
| Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic Ξ΄GABA<sub>A</sub> receptors. | Borland JM et al. | β | 2020 | β |
| Dopaminergic-GABAergic interplay and alcohol binge drinking. | Leggio GM et al. | β | 2019 | β |
| A Hepatocyte-Mimicking Antidote for Alcohol Intoxication. | Xu D et al. | β | 2018 | β |
| GABA<sub>A</sub> receptor: Positive and negative allosteric modulators. | Olsen RW | β | 2018 | β |
| The Cerebellar GABA<sub>A</sub>R System as a Potential Target for Treating Alcohol Use Disorder. | Rossi DJ et al. | β | 2018 | β |
| The Multidimensional Therapeutic Potential of Targeting the Brain Oxytocin System for the Treatment of Substance Use Disorders. | Bowen MT et al. | β | 2018 | β |
| The Ξ±6 subunit-containing GABA<sub>A</sub> receptor: A novel drug target for inhibition of trigeminal activation. | Fan PC et al. | β | 2018 | β |
| Catatonia Secondary to Sudden Clozapine Withdrawal: A Case with Three Repeated Episodes and a Literature Review. | Bilbily J et al. | β | 2017 | β |
| GABA<sub>A</sub> receptor subtype involvement in addictive behaviour. | Stephens DN et al. | β | 2017 | β |
| Rebalancing the Addicted Brain: Oxytocin Interference with the Neural Substrates of Addiction. | Bowen MT et al. | β | 2017 | β |
| A pharmacological assessment of agonists and modulators at Ξ±4Ξ²2Ξ³2 and Ξ±4Ξ²2Ξ΄ GABAA receptors: The challenge in comparing apples with oranges. | Ahring PK et al. | β | 2016 | β |
| Comparing the discriminative stimulus effects of modulators of GABAA receptors containing Ξ±4-Ξ΄ subunits with those of gaboxadol in rats. | Zanettini C et al. | β | 2016 | β |
| Ethanol Regulation of Synaptic GABAA Ξ±4 Receptors Is Prevented by Protein Kinase A Activation. | Carlson SL et al. | β | 2016 | β |
| Flumazenil decreases surface expression of Ξ±4Ξ²2Ξ΄ GABAA receptors by increasing the rate of receptor internalization. | Kuver A et al. | β | 2016 | β |
| Involvement of the GABAA Receptor in Age-Dependent Differences in Binge-Like Ethanol Intake. | Quoilin C et al. | β | 2016 | β |
| Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy. | Agusti A et al. | β | 2016 | β |
| To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABAA receptors modulators? | Chagraoui A et al. | β | 2016 | β |
| Advances in the pharmacology of lGICs auxiliary subunits. | Galaz P et al. | β | 2015 | β |
| Allosteric ligands and their binding sites define Ξ³-aminobutyric acid (GABA) type A receptor subtypes. | Olsen RW | β | 2015 | β |
| Allosteric modulation of GABAA receptors via multiple drug-binding sites. | Sieghart W | β | 2015 | β |
| Low Doses of Ethanol Enhance LTD-like Plasticity in Human Motor Cortex. | Fuhl A et al. | β | 2015 | β |
| Mini-Review: Effects of Ethanol on GABAA Receptor-Mediated Neurotransmission in the Cerebellar Cortex--Recent Advances. | Valenzuela CF et al. | β | 2015 | β |
| Oxytocin prevents ethanol actions at Ξ΄ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats. | Bowen MT et al. | β | 2015 | β |
| Alcohol selectivity of Ξ²3-containing GABAA receptors: evidence for a unique extracellular alcohol/imidazobenzodiazepine Ro15-4513 binding site at the Ξ±+Ξ²- subunit interface in Ξ±Ξ²3Ξ΄ GABAA receptors. | Wallner M et al. | β | 2014 | β |
| Analysis of Ξ³-aminobutyric acid (GABA) type A receptor subtypes using isosteric and allosteric ligands. | Olsen RW | β | 2014 | β |
| GABAA-R Ξ±4 subunits are required for the low dose locomotor stimulatory effect of alphaxalone, but not for several other behavioral responses to alphaxalone, etomidate or propofol. | Iyer SV et al. | β | 2014 | β |
| Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research. | Naito A et al. | β | 2014 | β |
| International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. | Christopoulos A et al. | β | 2014 | β |
| Spatial heterogeneity of the relation between resting-state connectivity and blood flow: an important consideration for pharmacological studies. | Khalili-Mahani N et al. | β | 2014 | β |
| A reinforcing circuit action of extrasynaptic GABAA receptor modulators on cerebellar granule cell inhibition. | Santhakumar V et al. | β | 2013 | β |
| A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA(A) receptors. | Jensen ML et al. | β | 2013 | β |
| GABAergic transmission in hepatic encephalopathy. | Sergeeva OA | β | 2013 | β |
| GABA<sub>A</sub> Receptors of Cerebellar Granule Cells in Culture: Interaction with Benzodiazepines. | Cupello A et al. | β | 2013 | β |
| Modulation of diazepam-insensitive GABA(A) receptors by micromolar concentrations of thyroxine and related compounds in vitro. | Ishibashi H et al. | β | 2013 | β |
| Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. | Carver CM et al. | β | 2013 | β |
| Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice. | Herman MA et al. | β | 2013 | β |
| Alpha4 subunit-containing GABAA receptors in the accumbens shell contribute to the reinforcing effects of alcohol. | Rewal M et al. | β | 2012 | β |
| A novel GABA(A) receptor pharmacology: drugs interacting with the Ξ±(+) Ξ²(-) interface. | Sieghart W et al. | β | 2012 | β |
| Effects of morphine and alcohol on functional brain connectivity during "resting state": a placebo-controlled crossover study in healthy young men. | Khalili-Mahani N et al. | β | 2012 | β |
| Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro. | Lieberman R et al. | β | 2012 | β |
| The genetics of substance dependence. | Wang JC et al. | β | 2012 | β |
| Zebrafish: a model for the study of addiction genetics. | Klee EW et al. | β | 2012 | β |
| Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution. | Howard RJ et al. | β | 2011 | β |
| GABA(A) receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. | Olsen RW et al. | β | 2011 | β |
| GABAA receptors in the posterior, but not anterior, ventral tegmental area mediate Ro15-4513-induced attenuation of binge-like ethanol consumption in C57BL/6J female mice. | MelΓ³n LC et al. | β | 2011 | β |
| Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow. | Khalili-Mahani N et al. | β | 2011 | β |
| Ro 15-4513 Antagonizes Alcohol-Induced Sedation in Mice Through Ξ±Ξ²Ξ³2-type GABA(A) Receptors. | Linden AM et al. | β | 2011 | β |
| The effects of hypoglycemic and alcoholic coma on the blood-brain barrier permeability. | Yorulmaz H et al. | β | 2011 | β |
| The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs. | Ramerstorfer J et al. | β | 2011 | β |
| Ξ±4-Containing GABA(A) Receptors are Required for Antagonism of Ethanol-Induced Motor Incoordination and Hypnosis by the Imidazobenzodiazepine Ro15-4513. | Iyer SV et al. | β | 2011 | β |
| Alcohol- and alcohol antagonist-sensitive human GABAA receptors: tracking Ξ΄ subunit incorporation into functional receptors. | Meera P et al. | β | 2010 | β |
| Ethanol acutely modulates mGluR1-dependent long-term depression in cerebellum. | Su LD et al. | β | 2010 | β |
| GABA(A) receptor subunit alteration-dependent diazepam insensitivity in the cerebellum of phospholipase C-related inactive protein knockout mice. | Mizokami A et al. | β | 2010 | β |
| Low-dose ethanol suppresses 17beta-estradiol activity in GH4C1 pituitary tumor cells. | Wang G et al. | β | 2010 | β |
| Molecular targets and mechanisms for ethanol action in glycine receptors. | Perkins DI et al. | β | 2010 | β |
| Pharmacological characterization of a novel positive modulator at alpha 4 beta 3 delta-containing extrasynaptic GABA(A) receptors. | Hoestgaard-Jensen K et al. | β | 2010 | β |
| Regulation of GABA(A) receptor subunit expression by pharmacological agents. | Uusi-Oukari M et al. | β | 2010 | β |
| Remarkable selectivity of the in vivo binding of [3H]Ro15-4513 to Ξ±5 subtype of benzodiazepine receptor in the living mouse brain. | Momosaki S et al. | β | 2010 | β |
| Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha4beta3delta and alpha4beta3 GABA A receptors expressed in HEK cells. | Meera P et al. | β | 2009 | β |
| GABA(A) receptors of cerebellar granule cells in culture: explanation of overall insensitivity to ethanol. | Gatta E et al. | β | 2009 | β |
| GABA A receptors: subtypes provide diversity of function and pharmacology. | Olsen RW et al. | β | 2009 | β |
| Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity. | Perkins DI et al. | β | 2009 | β |
| The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. | Kumar S et al. | β | 2009 | β |
| Comments on "Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABA(A) receptor subunit". | Otis TS | β | 2008 | β |
| Effects of ethanol on axon outgrowth and branching in developing rat cortical neurons. | Hoffman EJ et al. | β | 2008 | β |
| Ethanol modulates synaptic and extrasynaptic GABAA receptors in the thalamus. | Jia F et al. | β | 2008 | β |
| Ethanol selectively attenuates NMDAR-mediated synaptic transmission in the prefrontal cortex. | Weitlauf C et al. | β | 2008 | β |
| Ethanol's molecular targets. | Harris RA et al. | β | 2008 | β |
| GABA(A) receptors and alcohol. | Lobo IA et al. | β | 2008 | β |
| International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. | Olsen RW et al. | β | 2008 | β |
| Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice. | Chandra D et al. | β | 2008 | β |
| Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABAA receptors as an opportunity for drug development? | Wallner M et al. | β | 2008 | β |
| The role of GABA(A) receptors in the development of alcoholism. | Enoch MA | β | 2008 | β |
| Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol. | Helms CM et al. | β | 2008 | β |
| Does ethanol act preferentially via selected brain GABAA receptor subtypes? the current evidence is ambiguous. | Korpi ER et al. | β | 2007 | β |
| Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition. | Santhakumar V et al. | β | 2007 | β |
| Ethanol effects on GABA-gated current in a model of increased alpha4betadelta GABAA receptor expression depend on time course and preexposure to low concentrations of the drug. | Smith SS et al. | β | 2007 | β |
| Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABAA receptor subunit. | Botta P et al. | β | 2007 | β |
| GABAA receptor subtypes: the "one glass of wine" receptors. | Olsen RW et al. | β | 2007 | β |
| KCC2-deficient mice show reduced sensitivity to diazepam, but normal alcohol-induced motor impairment, gaboxadol-induced sedation, and neurosteroid-induced hypnosis. | Tornberg J et al. | β | 2007 | β |
| Low concentrations of ethanol do not affect radioligand binding to the delta-subunit-containing GABAA receptors in the rat brain. | Mehta AK et al. | β | 2007 | β |
| Mechanisms of neurosteroid interactions with GABA(A) receptors. | Akk G et al. | β | 2007 | β |
| Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. | Green ML et al. | β | 2007 | β |
| Stress, ethanol, and neuroactive steroids. | Biggio G et al. | β | 2007 | β |
| Studies of ethanol actions on recombinant delta-containing gamma-aminobutyric acid type A receptors yield contradictory results. | Borghese CM et al. | β | 2007 | β |
| Tonic for what ails us? high-affinity GABAA receptors and alcohol. | Lovinger DM et al. | β | 2007 | β |
| Alcohol-sensitive GABA receptors and alcohol antagonists. | Paul SM | β | 2006 | β |
| Lifelong ethanol consumption and brain regional GABAA receptor subunit mRNA expression in alcohol-preferring rats. | Sarviharju M et al. | β | 2006 | β |
| Low dose acute alcohol effects on GABA A receptor subtypes. | Wallner M et al. | β | 2006 | β |
| Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513. | Wallner M et al. | β | 2006 | β |
| Structure, pharmacology, and function of GABAA receptor subtypes. | Sieghart W | β | 2006 | β |