Steroid modulation of the GABAA receptor complex

Electrophysiological studies.

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)

83 Citations (Scopus)

Abstract

The effect of some endogenous and synthetic steroids on the operation of inhibitory and excitatory amino acid neurotransmitter receptors was examined. Anaesthetic pregnane steroids (e.g. alphaxalone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 alpha-pregnane-3 alpha,21-diol-20-one) potentiated GABAA receptor-mediated whole-cell currents recorded from bovine chromaffin cells. The threshold concentration for enhancement was 10-30 nM. Potentiation was stereoselective and was mediated by a steroid-induced prolongation of the burst duration of the GABA-activated channel. Additionally, the pregnane steroids directly activated the GABAA receptor. Both the potentiation and activation appear to be mediated through a site(s) distinct from the well-known barbiturate and benzodiazepine allosteric sites of the GABAA receptor. Intracellularly applied alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one had no discernible effects on the GABAA receptor, suggesting that the steroid binding site can only be accessed extracellularly. Unlike behaviourally depressant barbiturates, which modulate GABAA receptor function in a manner similar to that of the pregnane steroids, alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one show striking pharmacological selectivity. Voltage-clamp recordings from rat central neurons in culture indicate that pentobarbitone exerts its potentiating and GABA-mimetic effects over a range of concentrations which also depress currents mediated by glutamate receptor subtypes. In contrast, alphaxalone and several endogenous steroids greatly enhance responses to GABA, but have no direct effect on glutamate receptors. Such pharmacological selectivity, coupled with appropriate stereoselectivity of action, suggests that the GABAA receptor mediates some of the behavioural effects of synthetic and endogenous pregnane steroids.

Original languageEnglish
Title of host publicationCiba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity
Subtitle of host publicationCiba Foundation Symposium 153
EditorsDerek Chadwick, Kate Widdows
PublisherWiley
Pages56-82
Number of pages27
Volume153
ISBN (Electronic)9780470513989
ISBN (Print)9780471926894
DOIs
Publication statusPublished - 1990

Publication series

NameNovartis Foundation Symposia
PublisherWiley
ISSN (Electronic)1935-4657

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GABA-A Receptors
Steroids
Pregnanes
Glutamate Receptors
gamma-Aminobutyric Acid
GABA Agents
Pharmacology
Allosteric Site
Chromaffin Cells
Barbiturates
Neurotransmitter Receptor
Pentobarbital
Benzodiazepines
Anesthetics
Binding Sites
Neurons
alphaxalone

Cite this

Lambert, J. J., Peters, J. A., Sturgess, N. C., & Hales, T. G. (1990). Steroid modulation of the GABAA receptor complex: Electrophysiological studies. In D. Chadwick, & K. Widdows (Eds.), Ciba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity: Ciba Foundation Symposium 153 (Vol. 153, pp. 56-82). (Novartis Foundation Symposia). Wiley. https://doi.org/10.1002/9780470513989.ch4
Lambert, Jeremy J. ; Peters, John A. ; Sturgess, Nicholas C. ; Hales, Tim G. / Steroid modulation of the GABAA receptor complex : Electrophysiological studies. Ciba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity: Ciba Foundation Symposium 153. editor / Derek Chadwick ; Kate Widdows. Vol. 153 Wiley, 1990. pp. 56-82 (Novartis Foundation Symposia).
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Lambert, JJ, Peters, JA, Sturgess, NC & Hales, TG 1990, Steroid modulation of the GABAA receptor complex: Electrophysiological studies. in D Chadwick & K Widdows (eds), Ciba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity: Ciba Foundation Symposium 153. vol. 153, Novartis Foundation Symposia, Wiley, pp. 56-82. https://doi.org/10.1002/9780470513989.ch4

Steroid modulation of the GABAA receptor complex : Electrophysiological studies. / Lambert, Jeremy J.; Peters, John A.; Sturgess, Nicholas C.; Hales, Tim G.

Ciba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity: Ciba Foundation Symposium 153. ed. / Derek Chadwick; Kate Widdows. Vol. 153 Wiley, 1990. p. 56-82 (Novartis Foundation Symposia).

Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)

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T1 - Steroid modulation of the GABAA receptor complex

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N2 - The effect of some endogenous and synthetic steroids on the operation of inhibitory and excitatory amino acid neurotransmitter receptors was examined. Anaesthetic pregnane steroids (e.g. alphaxalone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 alpha-pregnane-3 alpha,21-diol-20-one) potentiated GABAA receptor-mediated whole-cell currents recorded from bovine chromaffin cells. The threshold concentration for enhancement was 10-30 nM. Potentiation was stereoselective and was mediated by a steroid-induced prolongation of the burst duration of the GABA-activated channel. Additionally, the pregnane steroids directly activated the GABAA receptor. Both the potentiation and activation appear to be mediated through a site(s) distinct from the well-known barbiturate and benzodiazepine allosteric sites of the GABAA receptor. Intracellularly applied alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one had no discernible effects on the GABAA receptor, suggesting that the steroid binding site can only be accessed extracellularly. Unlike behaviourally depressant barbiturates, which modulate GABAA receptor function in a manner similar to that of the pregnane steroids, alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one show striking pharmacological selectivity. Voltage-clamp recordings from rat central neurons in culture indicate that pentobarbitone exerts its potentiating and GABA-mimetic effects over a range of concentrations which also depress currents mediated by glutamate receptor subtypes. In contrast, alphaxalone and several endogenous steroids greatly enhance responses to GABA, but have no direct effect on glutamate receptors. Such pharmacological selectivity, coupled with appropriate stereoselectivity of action, suggests that the GABAA receptor mediates some of the behavioural effects of synthetic and endogenous pregnane steroids.

AB - The effect of some endogenous and synthetic steroids on the operation of inhibitory and excitatory amino acid neurotransmitter receptors was examined. Anaesthetic pregnane steroids (e.g. alphaxalone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 alpha-pregnane-3 alpha,21-diol-20-one) potentiated GABAA receptor-mediated whole-cell currents recorded from bovine chromaffin cells. The threshold concentration for enhancement was 10-30 nM. Potentiation was stereoselective and was mediated by a steroid-induced prolongation of the burst duration of the GABA-activated channel. Additionally, the pregnane steroids directly activated the GABAA receptor. Both the potentiation and activation appear to be mediated through a site(s) distinct from the well-known barbiturate and benzodiazepine allosteric sites of the GABAA receptor. Intracellularly applied alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one had no discernible effects on the GABAA receptor, suggesting that the steroid binding site can only be accessed extracellularly. Unlike behaviourally depressant barbiturates, which modulate GABAA receptor function in a manner similar to that of the pregnane steroids, alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one show striking pharmacological selectivity. Voltage-clamp recordings from rat central neurons in culture indicate that pentobarbitone exerts its potentiating and GABA-mimetic effects over a range of concentrations which also depress currents mediated by glutamate receptor subtypes. In contrast, alphaxalone and several endogenous steroids greatly enhance responses to GABA, but have no direct effect on glutamate receptors. Such pharmacological selectivity, coupled with appropriate stereoselectivity of action, suggests that the GABAA receptor mediates some of the behavioural effects of synthetic and endogenous pregnane steroids.

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Lambert JJ, Peters JA, Sturgess NC, Hales TG. Steroid modulation of the GABAA receptor complex: Electrophysiological studies. In Chadwick D, Widdows K, editors, Ciba Foundation Symposium 153 ‐ Steroids and Neuronal Activity: Steroids and Neuronal Activity: Ciba Foundation Symposium 153. Vol. 153. Wiley. 1990. p. 56-82. (Novartis Foundation Symposia). https://doi.org/10.1002/9780470513989.ch4