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Mol Pharmacol
2022 Feb 01;1012:68-77. doi: 10.1124/molpharm.121.000385.
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The Sulfated Steroids Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate Inhibit the α1β3γ2L GABAA Receptor by Stabilizing a Novel Nonconducting State.
Pierce SR
,
Germann AL
,
Steinbach JH
,
Akk G
.
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The GABAA receptor is inhibited by the endogenous sulfated steroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS). It has been proposed in previous work that these steroids act by enhancing desensitization of the receptor. Here, we have investigated the modulatory effects of the steroids on the human α1β3γ2L GABAA receptor. Using electrophysiology and quantitative model-based data analysis, we show that exposure to the steroid promotes occupancy of a nonconducting state that retains high affinity to the transmitter but whose properties differ from those of the classic, transmitter-induced desensitized state. From the analysis of the inhibitory actions of two combined steroids, we infer that PS and DHEAS act through shared or overlapping binding sites. SIGNIFICANCE STATEMENT: Previous work has proposed that sulfated neurosteroids inhibit the GABAA receptor by enhancing the rate of entry into the desensitized state. This study shows that the inhibitory steroids pregnenolone sulfate and dehydroepiandrosterone sulfate act through a common interaction site by stabilizing a distinct nonconducting state.
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,
Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABAA Receptor: Relating Occupancy to State Functions.
2020,
Pubmed
Akk,
GABA Type A Receptor Activation in the Allosteric Coagonist Model Framework: Relationship between EC50 and Basal Activity.
2018,
Pubmed
,
Xenbase
Chang,
Desensitization mechanism of GABA receptors revealed by single oocyte binding and receptor function.
2002,
Pubmed
,
Xenbase
Charalampopoulos,
Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging.
2006,
Pubmed
Chisari,
Visualizing pregnenolone sulfate-like modulators of NMDA receptor function reveals intracellular and plasma-membrane localization.
2019,
Pubmed
,
Xenbase
Corpéchot,
Characterization and measurement of dehydroepiandrosterone sulfate in rat brain.
1981,
Pubmed
Corpéchot,
Pregnenolone and its sulfate ester in the rat brain.
1983,
Pubmed
Demirgören,
Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor.
1991,
Pubmed
Eisenman,
Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.
2003,
Pubmed
,
Xenbase
Eisenman,
Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light.
2007,
Pubmed
Germann,
Steady-State Activation and Modulation of the Concatemeric α1β2γ2L GABAA Receptor.
2019,
Pubmed
,
Xenbase
Germann,
Steady-state activation and modulation of the synaptic-type α1β2γ2L GABAA receptor by combinations of physiological and clinical ligands.
2019,
Pubmed
,
Xenbase
Germann,
Analysis of Modulation of the ρ1 GABAA Receptor by Combinations of Inhibitory and Potentiating Neurosteroids Reveals Shared and Distinct Binding Sites.
2020,
Pubmed
,
Xenbase
Hansen,
Differential blockade of gamma-aminobutyric acid type A receptors by the neuroactive steroid dehydroepiandrosterone sulfate in posterior and intermediate pituitary.
1999,
Pubmed
Karlin,
On the application of "a plausible model" of allosteric proteins to the receptor for acetylcholine.
1967,
Pubmed
Laverty,
Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.
2017,
Pubmed
Le Foll,
Electrophysiological effects of various neuroactive steroids on the GABA(A) receptor in pituitary melanotrope cells.
1997,
Pubmed
Lingle,
Inactivation of BK channels mediated by the NH(2) terminus of the beta3b auxiliary subunit involves a two-step mechanism: possible separation of binding and blockade.
2001,
Pubmed
,
Xenbase
MONOD,
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
1965,
Pubmed
Majewska,
The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor.
1990,
Pubmed
Majewska,
Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons.
1988,
Pubmed
Majewska,
Pregnenolone-sulfate: an endogenous antagonist of the gamma-aminobutyric acid receptor complex in brain?
1987,
Pubmed
Michel,
New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology.
2020,
Pubmed
Mienville,
Pregnenolone sulfate antagonizes GABAA receptor-mediated currents via a reduction of channel opening frequency.
1989,
Pubmed
Monnet,
Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus.
1995,
Pubmed
Morgan,
Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in humans exposed to acute stress.
2004,
Pubmed
Park-Chung,
Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites.
1999,
Pubmed
,
Xenbase
Ritsner,
The clinical and therapeutic potentials of dehydroepiandrosterone and pregnenolone in schizophrenia.
2011,
Pubmed
Sachidanandan,
Inhibition of the GABAA Receptor by Sulfated Neurosteroids: A Mechanistic Comparison Study between Pregnenolone Sulfate and Dehydroepiandrosterone Sulfate.
2015,
Pubmed
Shen,
Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization.
2000,
Pubmed
Shin,
Analysis of GABAA Receptor Activation by Combinations of Agonists Acting at the Same or Distinct Binding Sites.
2019,
Pubmed
,
Xenbase
Shin,
The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity.
2017,
Pubmed
,
Xenbase
Smith,
Pregnenolone sulfate as a modulator of synaptic plasticity.
2014,
Pubmed
Spivak,
Desensitization and noncompetitive blockade of GABAA receptors in ventral midbrain neurons by a neurosteroid dehydroepiandrosterone sulfate.
1994,
Pubmed
Steinbach,
Applying the Monod-Wyman-Changeux Allosteric Activation Model to Pseudo-Steady-State Responses from GABAA Receptors.
2019,
Pubmed
Valenti,
Dehydroepiandrosterone sulfate and cognitive function in the elderly: The InCHIANTI Study.
2009,
Pubmed
Wagenmakers,
AIC model selection using Akaike weights.
2004,
Pubmed
Wang,
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
2002,
Pubmed
,
Xenbase
Wu,
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
1991,
Pubmed
Xu,
Competitive antagonists facilitate the recovery from desensitization of α1β2γ2 GABAA receptors expressed in Xenopus oocytes.
2016,
Pubmed
,
Xenbase
