Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Sci Rep
2019 Nov 05;91:15997. doi: 10.1038/s41598-019-52573-z.
Show Gene links
Show Anatomy links
Steady-state activation of the high-affinity isoform of the α4β2δ GABAA receptor.
Pierce SR
,
Senneff TC
,
Germann AL
,
Akk G
.
???displayArticle.abstract???
Activation of GABAA receptors consisting of α4, β2 (or β3), and δ subunits is a major contributor to tonic inhibition in several brain regions. The goal of this study was to analyze the function of the α4β2δ receptor in the presence of GABA and other endogenous and clinical activators and modulators under steady-state conditions. We show that the receptor has a high constitutive open probability (~0.1), but is only weakly activated by GABA that has a maximal peak open probability (POpen,peak) of 0.4, taurine (maximal POpen,peak = 0.4), or the endogenous steroid allopregnanolone (maximal POpen,peak = 0.2). The intravenous anesthetic propofol is a full agonist (maximal POpen,peak = 0.99). Analysis of currents using a cyclic three-state Resting-Active-Desensitized model indicates that the maximal steady-state open probability of the α4β2δ receptor is ~0.45. Steady-state open probability in the presence of combinations of GABA, taurine, propofol, allopregnanolone and/or the inhibitory steroid pregnenolone sulfate closely matched predicted open probability calculated assuming energetic additivity. The results suggest that the receptor is active in the presence of physiological concentrations of GABA and taurine, but, surprisingly, that receptor activity is only weakly potentiated by propofol.
Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001, Pubmed
Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001,
Pubmed
Akk,
Activation of GABA(A) receptors containing the alpha4 subunit by GABA and pentobarbital.
2004,
Pubmed
Akk,
GABA Type A Receptor Activation in the Allosteric Coagonist Model Framework: Relationship between EC50 and Basal Activity.
2018,
Pubmed
,
Xenbase
Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase
Brown,
Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.
2002,
Pubmed
Chandra,
GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol.
2006,
Pubmed
Dawidowicz,
Free and bound propofol concentrations in human cerebrospinal fluid.
2003,
Pubmed
Eaton,
γ-aminobutyric acid type A α4, β2, and δ subunits assemble to produce more than one functionally distinct receptor type.
2014,
Pubmed
,
Xenbase
Eaton,
Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol.
2016,
Pubmed
Eisenman,
Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.
2003,
Pubmed
,
Xenbase
Forman,
Mutations in the GABAA receptor that mimic the allosteric ligand etomidate.
2012,
Pubmed
,
Xenbase
Forman,
Monod-Wyman-Changeux allosteric mechanisms of action and the pharmacology of etomidate.
2012,
Pubmed
Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed
Germann,
Steady-state activation and modulation of the synaptic-type α1β2γ2L GABAA receptor by combinations of physiological and clinical ligands.
2019,
Pubmed
,
Xenbase
Germann,
Steady-State Activation and Modulation of the Concatemeric α1β2γ2L GABAA Receptor.
2019,
Pubmed
,
Xenbase
Hadley,
Rat alpha6beta2delta GABAA receptors exhibit two distinct and separable agonist affinities.
2007,
Pubmed
,
Xenbase
Hartiadi,
High and low GABA sensitivity α4β2δ GABAA receptors are expressed in Xenopus laevis oocytes with divergent stoichiometries.
2016,
Pubmed
,
Xenbase
Horikoshi,
Taurine and beta-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA.
1988,
Pubmed
,
Xenbase
Jia,
Taurine is a potent activator of extrasynaptic GABA(A) receptors in the thalamus.
2008,
Pubmed
Karim,
Low nanomolar GABA effects at extrasynaptic α4β1/β3δ GABA(A) receptor subtypes indicate a different binding mode for GABA at these receptors.
2012,
Pubmed
,
Xenbase
Keramidas,
Agonist-dependent single channel current and gating in alpha4beta2delta and alpha1beta2gamma2S GABAA receptors.
2008,
Pubmed
Kletke,
Partial agonism of taurine at gamma-containing native and recombinant GABAA receptors.
2013,
Pubmed
,
Xenbase
Liao,
Etomidate Effects on Desensitization and Deactivation of α4β3δ GABAA Receptors Inducibly Expressed in HEK293 TetR Cells.
2019,
Pubmed
Meera,
Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha4beta3delta and alpha4beta3 GABA A receptors expressed in HEK cells.
2009,
Pubmed
Meera,
Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA(A) receptors.
2011,
Pubmed
,
Xenbase
Molchanova,
Characteristics of basal taurine release in the rat striatum measured by microdialysis.
2004,
Pubmed
Mortensen,
Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.
2010,
Pubmed
Ochoa-de la Paz,
Differential modulation of human GABAC-ρ1 receptor by sulfur-containing compounds structurally related to taurine.
2018,
Pubmed
,
Xenbase
Porcello,
Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit.
2003,
Pubmed
Ruesch,
An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors.
2012,
Pubmed
,
Xenbase
Shin,
The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity.
2017,
Pubmed
,
Xenbase
Steinbach,
Applying the Monod-Wyman-Changeux Allosteric Activation Model to Pseudo-Steady-State Responses from GABAA Receptors.
2019,
Pubmed
Stell,
Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
2003,
Pubmed
Stórustovu,
Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2.
2006,
Pubmed
,
Xenbase
Tang,
Modulation of spontaneous and GABA-evoked tonic alpha4beta3delta and alpha4beta3gamma2L GABAA receptor currents by protein kinase A.
2010,
Pubmed
Wafford,
Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus.
2009,
Pubmed
Weill-Engerer,
Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients.
2002,
Pubmed
Weir,
Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics.
2017,
Pubmed
Wisden,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon.
1992,
Pubmed
Wongsamitkul,
Toward Understanding Functional Properties and Subunit Arrangement of α4β2δ γ-Aminobutyric Acid, Type A (GABAA) Receptors.
2016,
Pubmed
,
Xenbase
Zandy,
High sensitivity HPLC method for analysis of in vivo extracellular GABA using optimized fluorescence parameters for o-phthalaldehyde (OPA)/sulfite derivatives.
2017,
Pubmed
de Groote,
Exposure to novelty and forced swimming evoke stressor-dependent changes in extracellular GABA in the rat hippocampus.
2007,
Pubmed