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Molecular Pharmacology

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Research ArticleArticle

Site-Specific Fluorescence Reveals Distinct Structural Changes Induced in the Human ρ1 GABA Receptor by Inhibitory Neurosteroids

Ping Li, Alpa Khatri, John Bracamontes, David S. Weiss, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology April 2010, 77 (4) 539-546; DOI: https://doi.org/10.1124/mol.109.062885
Ping Li
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Alpa Khatri
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John Bracamontes
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David S. Weiss
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Joe Henry Steinbach
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Gustav Akk
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Abstract

The ρ1 GABA receptor is inhibited by a number of neuroactive steroids. A previous study (J Pharmacol Exp Ther 323:236–247, 2007) focusing on the electrophysiological effects of inhibitory steroids on the ρ1 receptor found that steroid inhibitors could be divided into three major groups based on how mutations to residues in the M2 transmembrane domain modified inhibition. It was proposed that the steroids act through distinct mechanisms. We selected representatives of the three groups (pregnanolone, tetrahydrodeoxycorticosterone, pregnanolone sulfate, allopregnanolone sulfate, and β-estradiol) and probed how these steroids, as well as the nonsteroidal inhibitor picrotoxinin, modify GABA-elicited fluorescence changes from the Alexa 546 C5 maleimide fluorophore attached to residues in the extracellular region of the receptor. The fluorophore responds with changes in quantum yield to changes in the environment, allowing it to probe for structural changes taking place during channel activation or modulation. The results indicate that the modulators have specific effects on fluorescence changes suggesting that distinct conformational changes accompany inhibition. The findings are consistent with the steroids acting as allosteric inhibitors of the ρ1 GABA receptor and support the hypothesis that divergent mechanisms underlie the action of inhibitory steroids on the ρ1 GABA receptor.

Footnotes

    fn-2
  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • fn-3
  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS35291]; National Institutes of Health National Institute of General Medical Sciences [Grant GM47969]; and National Institutes of Health National Institute of Environmental Health Sciences [Grant ES16350].

  • fn-4
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062885.

  • fn-5
  • ABBREVIATIONS:

    3α5βP
    pregnanolone
    3α5βPS
    pregnanolone sulfate
    3α5αPS
    allopregnanolone sulfate
    3α5βPOH
    tetrahydrodeoxycorticosterone
    ΔF
    fluorescence change
    A5m
    Alexa Fluor 546 C5 maleimide.

    • Received December 2, 2009.
    • Accepted January 8, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Site-Specific Fluorescence Reveals Distinct Structural Changes Induced in the Human ρ1 GABA Receptor by Inhibitory Neurosteroids

Ping Li, Alpa Khatri, John Bracamontes, David S. Weiss, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology April 1, 2010, 77 (4) 539-546; DOI: https://doi.org/10.1124/mol.109.062885

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Research ArticleArticle

Site-Specific Fluorescence Reveals Distinct Structural Changes Induced in the Human ρ1 GABA Receptor by Inhibitory Neurosteroids

Ping Li, Alpa Khatri, John Bracamontes, David S. Weiss, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology April 1, 2010, 77 (4) 539-546; DOI: https://doi.org/10.1124/mol.109.062885
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