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Cited by 138Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyIon channel regulation and function

Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunit

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Akk, Gustav, Bracamontes, John, Steinbach, Joe Henry·2001·The Journal of Physiology
DOI 10.1111/j.1469-7793.2001.0673e.xPMC PMC2278584
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Abstract

Neurosteroids are produced in the brain, and can have rapid actions on membrane channels of neurons. Pregnenolone sulfate (PS) is a sulfated neurosteroid which reduces the responses of the [gamma]-aminobutyric acid A (GABA(A)) receptor. We analysed the actions of PS on single-channel currents from recombinant GABA(A) receptors formed from [alpha]1, [beta]2 and [gamma]2L subunits. Currents were elicited by a concentration of GABA eliciting a half-maximal response (50 microM) and a saturating concentration (1 mM). PS reduced the duration of clusters of single-channel activity at either concentration of GABA. PS had no discernable effect on rapid processes: no effects were apparent on channel opening and closing, nor on GABA affinity, and a rapidly recovering desensitised state was not affected. Instead, PS produced a slowly developing block which occurred at a similar rate for receptors with open or closed channels and with one or two bound GABA molecules. The rate of block was independent of membrane potential, implying that the charged sulfate moiety does not move through the membrane field. Change in a specific residue near the intracellular end of the channel lining portion of the [alpha]1 subunit had a major effect on the rate of block. Mutation of the residue [alpha]1 V256S reduced the rate of block by 30-fold. A mutation at the homologous position of the [beta]2 subunit ([beta]2 A252S) had no effect, nor did a complementary mutation in the [gamma]2L subunit ([gamma]2L S266A). It seems likely that this residue is involved in a conformational change underlying block by PS, instead of forming part of the binding site for PS.

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  • A valine-to-serine mutation of the 2' residue of the α1-subunit M2 transmembrane domain (α1V256S) strongly diminished the ability of inhibitory steroids and steroid analogues to block the GABA_A receptor.

    “In the work with inhibitory steroids and steroid analogues, it was also shown that a valine-to-serine mutation of the 2 0 residue of the a1-subunit M2 transmembrane domain (a1V256S) strongly diminished the ability of these compounds to block the GABA A receptor (Akk et al., 2001;Li et al., 2006).”

    From The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat α1β2γ2L GABA<sub>A</sub>receptor (2008) · cites this paper as Akk et al., 2001

  • In contrast to inhibitory steroids and analogues whose effect is drastically diminished in the α1V256S mutant receptor, the inhibitory actions of fipronil were little affected by the α1V256S mutation.

    “But in contrast to these drugs whose effect is drastically diminished in the a1V256S mutant receptor, the inhibitory actions of fipronil were little affected by the a1V256S mutation.”

    From The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat α1β2γ2L GABA<sub>A</sub>receptor (2008) · cites this paper as Akk et al., 2001

  • The kinetic mechanism of action of fipronil is similar to that of an inhibitory neurosteroid, pregnenolone sulphate and some tricyclic neurosteroid analogues.

    “The kinetic mechanism of action of fipronil is similar to that of an inhibitory neurosteroid, pregnenolone sulphate and some tricyclic neurosteroid analogues (Akk et al., 2001;Li et al., 2006).”

    From The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat α1β2γ2L GABA<sub>A</sub>receptor (2008) · cites this paper as Akk et al., 2001

  • CA1 α1GABAARs play a role in memory consolidation.

    “Thus, these findings may suggest a role for CA1 α1 GABAARs in memory consolidation, providing temporal and anatomical specificity to early reports that the amnestic effects of diazepam were abolished in α1 (H101R) mice, in which diazepam does not bind to α1GABAARs [63].”

    From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [83]

  • Pregnenolone sulfate is a negative modulator of GABAARs including α1 GABAARs.

    “Pregnenolone sulfate is a negative modulator of GABAARs including α1 GABAARs [83].”

    From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [83]

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Authors
Akk, G., Bracamontes, J., & Steinbach, J. H.
Affiliations
Washington University in St. Louis (US)
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2001-05
Volume
532
Issue
3
Pages
673-684
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1111/j.1469-7793.2001.0673e.x
PMC
PMC2278584
OpenAlex
W2145087907
Cited by
137
References
49
Citations by year
2025: 3 · 2024: 6 · 2023: 11 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 6 · 2013: 6 · 2012: 4
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (P01GM047969, P01GM47969)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
pregnenolone sulfate, neurosteroids, GABAA receptor, alpha1 subunit, single-channel currents, desensitization, conformational change, channel gating
MeSH terms
Binding Sites, Cell Line, Estranes, gamma-Aminobutyric Acid, Humans, Kidney, Ligands, Membrane Potentials, Nitriles, Pentobarbital, Piperidines, Pregnenolone, Receptors, GABA-A, Transfection, Ion Channel Gating, Mutagenesis, Patch-Clamp Techniques, GABA Agonists, GABA Modulators

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