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Research ArticleArticle

Natural and Enantiomeric Etiocholanolone Interact with Distinct Sites on the Rat α1β2γ2L GABAA Receptor

Ping Li, John Bracamontes, Bryson W. Katona, Douglas F. Covey, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology June 2007, 71 (6) 1582-1590; DOI: https://doi.org/10.1124/mol.106.033407
Ping Li
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John Bracamontes
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Bryson W. Katona
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Douglas F. Covey
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Joe Henry Steinbach
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Gustav Akk
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Abstract

We have studied the ability of the androgen etiocholanolone and its enantiomer (ent-etiocholanolone) to modulate rat α1β2γ2L GABAA receptor function transiently expressed in human embryonic kidney cells. Studies on steroid enantiomer pairs can yield powerful new information on the pharmacology of steroid interactions with the GABAA receptor. Both steroids enhance currents elicited by GABA, but ent-etiocholanolone is much more powerful than etiocholanolone at producing potentiation. At a low GABA concentration (0.5 μM, <EC5), the presence of 10 μM ent-etiocholanolone potentiates whole-cell currents by almost 30-fold, whereas 10 μM etiocholanolone merely doubles the peak response. At higher GABA concentration (5 μM, ∼EC25), the potentiation curve for ent-etiocholanolone is positioned at lower concentrations than that for etiocholanolone. Single-channel kinetic analysis shows that exposure to etiocholanolone has a single effect on currents: the relative frequency of long openings is increased in the presence of steroid. But exposure to ent-etiocholanolone produces two kinetic effects: an increase in the relative frequency of long openings and a decrease in the frequency of long closed times. The presence of etiocholanolone does not inhibit potentiation by ent-etiocholanolone, suggesting that etiocholanolone is unable to interact with the sites through which ent-etiocholanolone modifies receptor function. The double mutation α1(N407A/Y410F) prevents potentiation by etiocholanolone but not by ent-etiocholanolone, and the α1(Q241A) and α1(I238N) point mutations fully abolish potentiation by etiocholanolone but not by ent-etiocholanolone. We conclude that etiocholanolone and its enantiomer interact with distinct sites on the α1β2γ2L GABAA receptor.

Footnotes

  • J.H.S. is the Russell and Mary Shelden Professor of Anesthesiology. This work was supported by National Institutes of Health grants AA14707 and GM47969.

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

  • doi:10.1124/mol.106.033407.

  • ABBREVIATIONS:ent-etiocholanolone, enantiomer of etiocholanolone; 3α5βP, pregnanolone.

    • Received December 11, 2006.
    • Accepted March 6, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Natural and Enantiomeric Etiocholanolone Interact with Distinct Sites on the Rat α1β2γ2L GABAA Receptor

Ping Li, John Bracamontes, Bryson W. Katona, Douglas F. Covey, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology June 1, 2007, 71 (6) 1582-1590; DOI: https://doi.org/10.1124/mol.106.033407

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Research ArticleArticle

Natural and Enantiomeric Etiocholanolone Interact with Distinct Sites on the Rat α1β2γ2L GABAA Receptor

Ping Li, John Bracamontes, Bryson W. Katona, Douglas F. Covey, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology June 1, 2007, 71 (6) 1582-1590; DOI: https://doi.org/10.1124/mol.106.033407
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