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3beta-hydroxypregna...
3beta-hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists
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- Wang, Mingde (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- He, Yejun (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Eisenman, Lawrence N (författare)
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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- Fields, Christopher (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Zeng, Chun-Min (författare)
- Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri
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- Mathews, Jose (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Benz, Ann (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Fu, Tao (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Zorumski, Erik (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Steinbach, Joe Henry (författare)
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri
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- Covey, Douglas F (författare)
- Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri
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- Zorumski, Charles F (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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- Mennerick, Steven (författare)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri Department of Neurology, Washington University School of Medicine, St. Louis, Missouri (creator_code:org_t)
- 2002
- 2002
- Engelska.
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 22:9, s. 3366-3375
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- neurosteroids; inhibitory postsynaptic current; GABAA receptors; pregnenolone sulfate; anesthetic; hippocampal culture
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Wang, Mingde
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He, Yejun
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Eisenman, Lawren ...
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Fields, Christop ...
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Zeng, Chun-Min
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Mathews, Jose
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visa fler...
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Benz, Ann
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Fu, Tao
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Zorumski, Erik
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Steinbach, Joe H ...
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Covey, Douglas F
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Zorumski, Charle ...
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Mennerick, Steve ...
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