Source:http://linkedlifedata.com/resource/pubmed/id/11978813
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
2002-4-29
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| pubmed:abstractText |
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.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Flumazenil,
http://linkedlifedata.com/resource/pubmed/chemical/GABA Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/GABA Modulators,
http://linkedlifedata.com/resource/pubmed/chemical/GABA-A Receptor Antagonists,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxysteroids,
http://linkedlifedata.com/resource/pubmed/chemical/Lorazepam,
http://linkedlifedata.com/resource/pubmed/chemical/Pregnanes,
http://linkedlifedata.com/resource/pubmed/chemical/Pregnenolone,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, GABA-A,
http://linkedlifedata.com/resource/pubmed/chemical/gamma-Aminobutyric Acid,
http://linkedlifedata.com/resource/pubmed/chemical/pregnenolone sulfate
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
1529-2401
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| pubmed:author |
pubmed-author:BenzAnnA,
pubmed-author:CoveyDouglas FDF,
pubmed-author:EisenmanLawrence NLN,
pubmed-author:FieldsChristopherC,
pubmed-author:HeYejunY,
pubmed-author:MAV CVC,
pubmed-author:MathewsJoseJ,
pubmed-author:MennerickStevenS,
pubmed-author:SteinbachJoe HenryJH,
pubmed-author:WangMingdeM,
pubmed-author:ZengChun-MinCM,
pubmed-author:ZorumskiCharles FCF,
pubmed-author:ZorumskiErikE
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| pubmed:issnType |
Electronic
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| pubmed:day |
1
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| pubmed:volume |
22
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
3366-75
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:11978813-Amino Acid Substitution,
pubmed-meshheading:11978813-Animals,
pubmed-meshheading:11978813-Cells, Cultured,
pubmed-meshheading:11978813-Dose-Response Relationship, Drug,
pubmed-meshheading:11978813-Flumazenil,
pubmed-meshheading:11978813-GABA Antagonists,
pubmed-meshheading:11978813-GABA Modulators,
pubmed-meshheading:11978813-GABA-A Receptor Antagonists,
pubmed-meshheading:11978813-Hydroxysteroids,
pubmed-meshheading:11978813-Lorazepam,
pubmed-meshheading:11978813-Oocytes,
pubmed-meshheading:11978813-Patch-Clamp Techniques,
pubmed-meshheading:11978813-Pregnanes,
pubmed-meshheading:11978813-Pregnenolone,
pubmed-meshheading:11978813-Protein Subunits,
pubmed-meshheading:11978813-Rats,
pubmed-meshheading:11978813-Rats, Sprague-Dawley,
pubmed-meshheading:11978813-Receptors, GABA-A,
pubmed-meshheading:11978813-Structure-Activity Relationship,
pubmed-meshheading:11978813-Synapses,
pubmed-meshheading:11978813-Xenopus laevis,
pubmed-meshheading:11978813-gamma-Aminobutyric Acid
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| pubmed:year |
2002
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| pubmed:articleTitle |
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
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| pubmed:affiliation |
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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