3β-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABA A Receptor Antagonists

Mingde Wang, Yejun He, Lawrence N. Eisenman, Christopher Fields, Chun Min Zeng, Jose Mathews, Ann Benz, Tao Fu, Erik Zorumski, Joe Henry Steinbach, Douglas F. Covey, Charles F. Zorumski, Steven Mennerick

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115 Scopus citations

Abstract

Endogenous neurosteroids have rapid actions on ion channels, particularly GABAA receptors, which are potentiated by nanomolar concentrations of 3α-hydroxypregnane neurosteroids. Previous evidence suggests that 3β-hydroxypregnane steroids may competitively antagonize potentiation induced by their 3α diastereomers. Because of the potential importance of antagonists as experimental and clinical tools, we characterized the functional effect of 3β-hydroxysteroids. Although 3β-hydroxysteroids reduced the potentiation induced by 3α-hydroxysteroids, 3β-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 3β-hydroxysteroids. 3β-Hydroxysteroids are also direct, noncompetitive GABAA receptor antagonists. 3β-Hydroxysteroids coapplied with GABA significantly inhibited responses to ≥15 μm GABA. The profile of block was similar to that exhibited by sulfated steroids, known blockers of GABAA receptors. This direct, noncompetitive effect of 3β-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 3β-hydroxysteroids on GABAA responses and the reduction of potentiating steroid effects. At concentrations that had little effect on GABAergic synaptic currents, 3β-hydroxysteroids and low concentrations of sulfated steroids significantly reversed the potentiation of synaptic currents induced by 3α-hydroxysteroids. We conclude that 3β-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABAA receptors. Nevertheless, these steroids may be useful functional blockers of potentiating steroids when used at concentrations that do not affect baseline neurotransmission.

Original languageEnglish
Pages (from-to)3366-3375
Number of pages10
JournalJournal of Neuroscience
Volume22
Issue number9
StatePublished - May 1 2002

Keywords

  • Anesthetic
  • GABA receptors
  • Hippocampal culture
  • Inhibitory postsynaptic current
  • Neurosteroids
  • Pregnenolone sulfate

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    Wang, M., He, Y., Eisenman, L. N., Fields, C., Zeng, C. M., Mathews, J., Benz, A., Fu, T., Zorumski, E., Steinbach, J. H., Covey, D. F., Zorumski, C. F., & Mennerick, S. (2002). 3β-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABA A Receptor Antagonists. Journal of Neuroscience, 22(9), 3366-3375.