Neurosteroids act on recombinant human GABAA receptors

  title={Neurosteroids act on recombinant human GABAA receptors},
  author={Giulia Puia and Maria Rita Santi and Stefano Vicini and Dolan B. Pritchett and Robert H. Purdy and Steven M Paul and P. H. Seeburg and Erminio Costa},

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Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor

The molecular mechanisms underpinning the non-genomic effect of agonist and antagonist neurosteroids will be discussed with particular emphasis being given to the role of GABA A receptor isoforms.

The Selective Interaction of Neurosteroids with the GABA A Receptor

It was not until Harrison and Simmonds demonstrated that a synthetic steroidal anesthetic, alphaxalone (3α-hydroxy-5α-pregnane-11,20-dione), selectively enhanced the interaction of GABA with the GABAA receptor, that a logical mechanism to explain the behavioral effects of these compounds emerged.

Steroid Modulation of GABAA Receptors

In electrophysiological, tracer-flux and radioligand binding studies, such steroids were found to be more potent than alphaxalone in potentiating the action of agonists at the GABAA receptor and allosteric interactions with established binding sites for other modulators were revealed.

3β-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAA Receptor Antagonists

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The results suggest that certain naturally occurring steroids potentiate the actions of GABA and, additionally, directly activate the GABAA receptor.

Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.

Two metabolites of the steroid hormones progesterone and deoxycorticosterone are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons, which may explain the ability of certain steroid hormones to rapidly alter neuronal excitability.

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Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s) as well as modulating GABA receptor-mediated 36Cl- uptake.

Synthesis, metabolism, and pharmacological activity of 3 alpha-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes.

Molecular modeling of the active steroids based on quantitative structure-activity relationships provides evidence to support the stereospecificity of the binding interactions and suggests that there may be more than one type of steroid binding site associated with the GABAA-receptor-mediated chloride ionophore.

Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology

The isolation of a cloned cDNA encoding a new GABAA receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS.

Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids

The results obtained with combinations of steroids and barbiturates in the ligand binding assay appear inconsistent with the two classes of compound interacting with a common site to modulate the GABAA receptor activity.

Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action.

In vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by [35S]-t-butylbicyclophosphorothionate reveal additional structural requirements necessary for activity, providing additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.

Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex.

Comparison of the structure-activity relationship data obtained in this study with those for steroid-induced general anesthesia strongly suggests that steroidal anesthesia may result from the interaction between steroids and the GABAA receptor.

Structural and functional basis for GABAA receptor heterogeneity

Two additional cDNAs encoding two additional GABAA receptor α-subunits are isolated, confirming the heterogeneous nature of the receptor/chloride channel complex and demonstrating the molecular basis for it.

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