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.
J Neurosci
2002 May 01;229:3366-75. doi: 20026342.
Show Gene links
Show Anatomy links
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
Wang M, He Y, Eisenman LN, Fields C, Zeng CM, Mathews J, Benz A, Fu T, Zorumski E, Steinbach JH, Covey DF, Zorumski CF, Mennerick S.
???displayArticle.abstract???
Endogenous neurosteroids have rapid actions on ion channels, particularly GABA(A) receptors, which are potentiated by nanomolar concentrations of 3alpha-hydroxypregnane neurosteroids. Previous evidence suggests that 3beta-hydroxypregnane steroids may competitively antagonize potentiation induced by their 3alpha diastereomers. Because of the potential importance of antagonists as experimental and clinical tools, we characterized the functional effect of 3beta-hydroxysteroids. Although 3beta-hydroxysteroids reduced the potentiation induced by 3alpha-hydroxysteroids, 3beta-hydroxysteroids acted noncompetitively with respect to potentiating steroids and inhibited the largest degrees of potentiation most effectively. Potentiation by high concentrations of barbiturates was also reduced by 3beta-hydroxysteroids. 3beta-Hydroxysteroids are also direct, noncompetitive GABA(A) receptor antagonists. 3beta-Hydroxysteroids coapplied with GABA significantly inhibited responses to > or =15 microm GABA. The profile of block was similar to that exhibited by sulfated steroids, known blockers of GABA(A) receptors. This direct, noncompetitive effect of 3beta-hydroxysteroids was sufficient to account for the apparent antagonism of potentiating steroids. Mutated receptors exhibiting decreased sensitivity to sulfated steroid block were insensitive to both the direct effects of 3beta-hydroxysteroids on GABA(A) responses and the reduction of potentiating steroid effects. At concentrations that had little effect on GABAergic synaptic currents, 3beta-hydroxysteroids and low concentrations of sulfated steroids significantly reversed the potentiation of synaptic currents induced by 3alpha-hydroxysteroids. We conclude that 3beta-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABA(A) receptors. Nevertheless, these steroids may be useful functional blockers of potentiating steroids when used at concentrations that do not affect baseline neurotransmission.
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 Barker,
Potentiation of gamma-aminobutyric-acid-activated chloride conductance by a steroid anaesthetic in cultured rat spinal neurones.
1987,
Pubmed Bekkers,
Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture.
1991,
Pubmed Covey,
Recent developments in structure-activity relationships for steroid modulators of GABA(A) receptors.
2001,
Pubmed Demirgören,
Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor.
1991,
Pubmed Garrett,
Enhancement of gamma-aminobutyric acidA receptor activity by alpha-chloralose.
1998,
Pubmed
,
Xenbase Gasior,
Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders.
1999,
Pubmed Han,
Neurosteroid analogues. 4. The effect of methyl substitution at the C-5 and C-10 positions of neurosteroids on electrophysiological activity at GABAA receptors.
1996,
Pubmed Jones,
Desensitized states prolong GABAA channel responses to brief agonist pulses.
1995,
Pubmed Jones,
Shaping of IPSCs by endogenous calcineurin activity.
1997,
Pubmed Kokate,
Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation.
1994,
Pubmed Le Foll,
Electrophysiological effects of various neuroactive steroids on the GABA(A) receptor in pituitary melanotrope cells.
1997,
Pubmed Macdonald,
GABAA receptor channels.
1994,
Pubmed Maconochie,
How quickly can GABAA receptors open?
1994,
Pubmed Maitra,
Modulation of GABA(A) receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABA(A) receptor isoforms.
1998,
Pubmed
,
Xenbase Majewska,
Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance.
1992,
Pubmed Majewska,
Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons.
1988,
Pubmed Mennerick,
Passive and synaptic properties of hippocampal neurons grown in microcultures and in mass cultures.
1995,
Pubmed Mennerick,
Effects on gamma-aminobutyric acid (GABA)(A) receptors of a neuroactive steroid that negatively modulates glutamate neurotransmission and augments GABA neurotransmission.
2001,
Pubmed
,
Xenbase Mienville,
Pregnenolone sulfate antagonizes GABAA receptor-mediated currents via a reduction of channel opening frequency.
1989,
Pubmed Park-Chung,
Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
1997,
Pubmed
,
Xenbase Park-Chung,
Sulfated and unsulfated steroids modulate gamma-aminobutyric acidA receptor function through distinct sites.
1999,
Pubmed
,
Xenbase Pignataro,
Epipregnanolone acts as a partial agonist on a common neurosteroid modulatory site of the GABA(A) receptor complex in avian CNS.
1997,
Pubmed Poisbeau,
Modulation of GABAA receptor-mediated IPSCs by neuroactive steroids in a rat hypothalamo-hypophyseal coculture model.
1997,
Pubmed Prince,
5 beta-pregnan-3 beta-ol-20-one, a specific antagonist at the neurosteroid site of the GABAA receptor-complex.
1992,
Pubmed Prince,
Differential antagonism by epipregnanolone of alphaxalone and pregnanolone potentiation of [3H]flunitrazepam binding suggests more than one class of binding site for steroids at GABAA receptors.
1993,
Pubmed Puia,
Neurosteroids act on recombinant human GABAA receptors.
1990,
Pubmed Shen,
Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization.
2000,
Pubmed Turner,
Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.
1989,
Pubmed Wang,
The inhibitory effects of allopregnanolone and pregnanolone on the population spike, evoked in the rat hippocampal CA1 stratum pyramidale in vitro, can be blocked selectively by epiallopregnanolone.
2000,
Pubmed Woodward,
Effects of steroids on gamma-aminobutyric acid receptors expressed in Xenopus oocytes by poly(A)+ RNA from mammalian brain and retina.
1992,
Pubmed
,
Xenbase Zaman,
Effects of subunit types of the recombinant GABAA receptor on the response to a neurosteroid.
1992,
Pubmed
,
Xenbase Zorumski,
Enantioselective modulation of GABAergic synaptic transmission by steroids and benz[e]indenes in hippocampal microcultures.
1998,
Pubmed
