A steroid recognition site is functionally coupled to an expressed GABAA-benzodiazepine receptor

doi:10.1016/0922-4106(90)90201-8

European Journal of Pharmacology: Molecular Pharmacology

Volume 188, Issue 6, 12 June 1990, Pages 403-406

https://doi.org/10.1016/0922-4106(90)90201-8 Get rights and content

Abstract

Pregnane steroids, particularly 3α-hydroxylated metabolites of progesterone, are known to have rapid and profound effects on brain excitability. Recent evidence suggests that the γ-aminobutyric acid (GABA_A)-benzodiazepine receptor-Cl⁻ ionophore complex may mediate these actions. The data further suggest that these steroids modulate the complex through a novel site independent of other known sites on the complex. The hypothesis that this site is on the GABA_A-benzodiazepine receptor-Cl⁻ ionophore complex is tested in the present study by determining its presence on transiently expressed GABA_A-benzodiazepine receptors.

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Many behavioral effects of neuroactive steroids are mediated by GABA_A receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced > 80% pregnanolone-lever responding. In contrast, neither morphine nor the negative GABA_A modulator β-CCE substituted for pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced < 20% pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABA_A modulators, and not morphine or β-CCE, for pregnanolone in all rats suggests that positive modulation of GABA_A receptors is important in the discriminative stimulus effects of pregnanolone. Although pregnanolone might have actions at other receptors, in addition to actions at GABA_A receptors, substitution of ethanol for pregnanolone only in some rats suggests that the mechanisms of action of pregnanolone and ethanol overlap, but are not identical.
Neurosteroid regulation of central nervous system development
2007, Pharmacology and Therapeutics
Neurosteroids are a relatively new class of neuroactive compounds brought to prominence in the past 2 decades. Despite knowing of their presence in the nervous system of various species for over 20 years and knowing of their functions as GABA_A and N-methyl-d-aspartate (NMDA) ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of 4 distinct neurosteroids: pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone (DHEA).
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To compare mRNA and protein levels of proenkephalin A (PEA) and γ-aminobutyric acid A receptor π subunit (πGABA-R) in human secretory endometrium before and during receptivity and to determine the cell phenotypes where they are expressed.
Prospective and observational, comparing prereceptive vs. receptive stages of secretory endometrium within the same nonconceptional menstrual cycle.
University and non-governmental organization (NGO)–based academic and clinical-research facilities.
Seven healthy, multiparous, surgically sterilized women with spontaneous regular menstrual cycles.
Endometrial biopsies were obtained on LH+3 and LH+7 within the same cycle.
Levels of PEA and πGABA-R mRNA were determined by real-time PCR, and protein presence, by immunofluorescence.
The mRNA level of PEA fell, whereas that of πGABA-R increased, during endometrial receptivity. Positive immunostaining of PEA was found in the luminal and glandular epithelium, whereas that of πGABA-R was in luminal epithelium and stromal cells.
The discrete cell-phenotype localization and timing of the changes in the level of PEA and of πGABA-R mRNA and protein suggest an important role for these molecules in switching the human endometrium from a refractory to a receptive state.
Identification of 3β,5β-tetrahydroprogesterone, a progesterone metabolite, and its stimulatory action on preoptic neurons in the avian brain
2004, Brain Research
Citation Excerpt :
The action of 3β,5β-THP may be nongenomic rather than genomic, because 3β,5β-THP increased rapidly the firing activity of preoptic neurons. In mammals, progesterone and 3α,5α-THP are thought to mediate their actions through ion-gated channel receptors, such as GABAA and glycine [16,31,33,34,40,54]. 3α,5α-THP is considered to be a positive allosteric modulator of GABAA receptor [19,20,37,42].
We have demonstrated recently that the quail brain possesses the cholesterol side-chain cleavage enzyme (cytochrome P450scc) and 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴-isomerase (3β-HSD) and produces pregnenolone, pregnenolone sulfate and progesterone from cholesterol. The present study was therefore conducted to investigate progesterone metabolism in the brain of adult male quails. Employing biochemical techniques combined with HPLC and TLC analyses, the conversion of progesterone to 3β,5β-tetrahydroprogesterone (3β,5β-THP) via 5β-dihydroprogesterone (5β-DHP) was found in the brain. There was a clear regional difference in progesterone metabolism. The formation of 3β,5β-THP was high in the diencephalon and cerebrum and low in the cerebellum. Based on such a region-dependent formation of 3β,5β-THP, the action of this progesterone metabolite on preoptic neurons in the diencephalon was then investigated electrophysiologically using a brain slice preparation of the adult male. 3β,5β-THP significantly increased, in a dose-related way, the spontaneous firing activity of subsets of preoptic neurons. The stimulatory effect of 3β,5β-THP was greater than that of progesterone and its threshold concentration ranged between 10⁻⁶ and 3×10⁻⁶ M. In 33% of cells in the preoptic area, however, 3β,5β-THP did not change the spontaneous firing activity even at the high concentration, 10⁻⁵ M. Because preoptic neurons are considered to be involved in the regulation of a variety of male reproductive behaviors, 3β,5β-THP may regulate some reproductive behavior through the mechanism that provokes such a stimulation.
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Short communicationA steroid recognition site is functionally coupled to an expressed GABAA-benzodiazepine receptor

Abstract

European J. Pharmacol.

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

J. Pharmacol. Exp. Ther.

Structure-activity relationships for steroid interaction with the gamma-aminobutyric acid-A receptor complex

J. Pharmacol. Exp. Ther.

Structural and functional basis for GABAA receptor heterogeneity

Nature

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

Science

Short communication
A steroid recognition site is functionally coupled to an expressed GABA_A-benzodiazepine receptor

Structural and functional basis for GABA_A receptor heterogeneity