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Mol Pharmacol
2014 Dec 01;866:635-46. doi: 10.1124/mol.114.093773.
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Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.
Naito A
,
Muchhala KH
,
Asatryan L
,
Trudell JR
,
Homanics GE
,
Perkins DI
,
Davies DL
,
Alkana RL
.
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A critical obstacle to developing effective medications to prevent and/or treat alcohol use disorders is the lack of specific knowledge regarding the plethora of molecular targets and mechanisms underlying alcohol (ethanol) action in the brain. To identify the role of individual receptor subunits in ethanol-induced behaviors, we developed a novel class of ultra-sensitive ethanol receptors (USERs) that allow activation of a single receptor subunit population sensitized to extremely low ethanol concentrations. USERs were created by mutating as few as four residues in the extracellular loop 2 region of glycine receptors (GlyRs) or γ-aminobutyric acid type A receptors (GABA(A)Rs), which are implicated in causing many behavioral effects linked to ethanol abuse. USERs, expressed in Xenopus oocytes and tested using two-electrode voltage clamp, demonstrated an increase in ethanol sensitivity of 100-fold over wild-type receptors by significantly decreasing the threshold and increasing the magnitude of ethanol response, without altering general receptor properties including sensitivity to the neurosteroid, allopregnanolone. These profound changes in ethanol sensitivity were observed across multiple subunits of GlyRs and GABA(A)Rs. Collectively, our studies set the stage for using USER technology in genetically engineered animals as a unique tool to increase understanding of the neurobiological basis of the behavioral effects of ethanol.
Adermark,
Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors.
2011, Pubmed
Adermark,
Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors.
2011,
Pubmed
Aguayo,
Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons.
1994,
Pubmed
Aston-Jones,
Recent advances in optogenetics and pharmacogenetics.
2013,
Pubmed
Blednov,
Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol.
2010,
Pubmed
Blednov,
GABAA receptor alpha 1 and beta 2 subunit null mutant mice: behavioral responses to ethanol.
2003,
Pubmed
Blednov,
Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive α2-containing GABA(A) receptors.
2011,
Pubmed
,
Xenbase
Bloomenthal,
Biphasic modulation of the strychnine-sensitive glycine receptor by Zn2+.
1994,
Pubmed
Borghese,
An isoflurane- and alcohol-insensitive mutant GABA(A) receptor alpha(1) subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice.
2006,
Pubmed
,
Xenbase
Bouchery,
Economic costs of excessive alcohol consumption in the U.S., 2006.
2011,
Pubmed
Brickley,
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
2001,
Pubmed
Chandra,
Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice.
2008,
Pubmed
Chen,
Role of glycine receptors in glycine-induced LTD in hippocampal CA1 pyramidal neurons.
2011,
Pubmed
Crawford,
Roles for loop 2 residues of alpha1 glycine receptors in agonist activation.
2008,
Pubmed
,
Xenbase
Crawford,
Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
2007,
Pubmed
,
Xenbase
Davies,
Multiple sites of ethanol action in alpha1 and alpha2 glycine receptors suggested by sensitivity to pressure antagonism.
2004,
Pubmed
,
Xenbase
Davies,
Ethanol potentiation of glycine receptors expressed in Xenopus oocytes antagonized by increased atmospheric pressure.
2003,
Pubmed
,
Xenbase
Deitrich,
Mechanism of action of ethanol: initial central nervous system actions.
1989,
Pubmed
Delaney,
Differential expression of glycine receptor subunits in the rat basolateral and central amygdala.
2010,
Pubmed
Dutertre,
Inhibitory glycine receptors: an update.
2012,
Pubmed
Eichler,
Splice-specific roles of glycine receptor alpha3 in the hippocampus.
2009,
Pubmed
Evers,
A synthetic 18-norsteroid distinguishes between two neuroactive steroid binding sites on GABAA receptors.
2010,
Pubmed
,
Xenbase
Follesa,
Neurosteroids, GABAA receptors, and ethanol dependence.
2006,
Pubmed
Grant,
The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002.
2004,
Pubmed
Grobin,
The role of GABA(A) receptors in the acute and chronic effects of ethanol.
1998,
Pubmed
Hanchar,
Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors.
2006,
Pubmed
Hanchar,
Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity.
2005,
Pubmed
,
Xenbase
Harris,
Ethanol's molecular targets.
2008,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hodge,
5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking.
2004,
Pubmed
Homanics,
A gain-of-function mutation in the GABA receptor produces synaptic and behavioral abnormalities in the mouse.
2005,
Pubmed
Howard,
Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution.
2011,
Pubmed
Johnson,
Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings.
2008,
Pubmed
Jonsson,
Changes in glycine receptor subunit expression in forebrain regions of the Wistar rat over development.
2012,
Pubmed
Kamens,
Modulation of ethanol consumption by genetic and pharmacological manipulation of nicotinic acetylcholine receptors in mice.
2010,
Pubmed
Kamens,
The nicotinic acetylcholine receptor partial agonist varenicline increases the ataxic and sedative-hypnotic effects of acute ethanol administration in C57BL/6J mice.
2010,
Pubmed
Kelm,
Ethanol-enhanced GABA release: a focus on G protein-coupled receptors.
2011,
Pubmed
Knapp,
Zacopride, a 5-HT3 receptor antagonist, reduces voluntary ethanol consumption in rats.
1992,
Pubmed
Kumar,
The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress.
2009,
Pubmed
Laube,
Modulation by zinc ions of native rat and recombinant human inhibitory glycine receptors.
1995,
Pubmed
,
Xenbase
Liang,
Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells.
2008,
Pubmed
Litten,
Medications development to treat alcohol dependence: a vision for the next decade.
2012,
Pubmed
Little,
Mechanisms that may underlie the behavioural effects of ethanol.
1991,
Pubmed
Lobo,
GABA(A) receptors and alcohol.
2008,
Pubmed
Luisi,
Serum allopregnanolone levels in pregnant women: changes during pregnancy, at delivery, and in hypertensive patients.
2000,
Pubmed
Maksay,
Dual cooperative allosteric modulation of binding to ionotropic glycine receptors.
2002,
Pubmed
Mascia,
Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics.
1996,
Pubmed
,
Xenbase
Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase
Mihic,
A single amino acid of the human gamma-aminobutyric acid type A receptor gamma 2 subunit determines benzodiazepine efficacy.
1994,
Pubmed
,
Xenbase
Mihic,
Anaesthetic concentrations of alcohols potentiate GABAA receptor-mediated currents: lack of subunit specificity.
1994,
Pubmed
,
Xenbase
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Moore,
Trace and contextual fear conditioning is enhanced in mice lacking the alpha4 subunit of the GABA(A) receptor.
2010,
Pubmed
Morrow,
Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites.
1990,
Pubmed
Naylor,
Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects.
2010,
Pubmed
Ogden,
Effects of alcohol and other drugs on driver performance.
2004,
Pubmed
Olsen,
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
2008,
Pubmed
Olsen,
GABAA receptor subtypes: the "one glass of wine" receptors.
2007,
Pubmed
Peng,
GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain.
2002,
Pubmed
Perkins,
Targets for ethanol action and antagonism in loop 2 of the extracellular domain of glycine receptors.
2008,
Pubmed
,
Xenbase
Perkins,
Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors.
2012,
Pubmed
,
Xenbase
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Ponomarev,
Transcriptional signatures of cellular plasticity in mice lacking the alpha1 subunit of GABAA receptors.
2006,
Pubmed
Rehm,
Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders.
2009,
Pubmed
Smith,
GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid.
1998,
Pubmed
Trudell,
Alcohol dependence: molecular and behavioral evidence.
2014,
Pubmed
Turner,
Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.
1989,
Pubmed
Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase
Weltzien,
Distribution of the glycine receptor β-subunit in the mouse CNS as revealed by a novel monoclonal antibody.
2012,
Pubmed
Werner,
Knockin mice with ethanol-insensitive alpha1-containing gamma-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol.
2006,
Pubmed
