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Research ArticleCELLULAR AND MOLECULAR

Neuroactive Steroid Interactions with Voltage-Dependent Anion Channels: Lack of Relationship to GABAA Receptor Modulation and Anesthesia

Ramin Darbandi-Tonkabon, Brad D. Manion, William R. Hastings, William J. Craigen, Gustav Akk, John R. Bracamontes, Yejun He, Tatiana V. Sheiko, Joseph H. Steinbach, Steven J. Mennerick, Douglas F. Covey and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 502-511; DOI: https://doi.org/10.1124/jpet.103.058123
Ramin Darbandi-Tonkabon
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Brad D. Manion
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William R. Hastings
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William J. Craigen
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Gustav Akk
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John R. Bracamontes
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Yejun He
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Tatiana V. Sheiko
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Joseph H. Steinbach
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Steven J. Mennerick
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Douglas F. Covey
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Alex S. Evers
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Abstract

Neuroactive steroids modulate the function of γ-aminobutyric acid type A (GABAA) receptors in brain; this is the presumed basis of their action as anesthetics. In a previous study using the neuroactive steroid analog, (3α,5β)-6-azi-3-hydroxypregnan-20-one (6-AziP), as a photoaffinity-labeling reagent, we showed that voltage-dependent anion channel-1 (VDAC-1) was the predominant protein labeled in brain. Antisera to VDAC-1 were shown to coimmunoprecipitate GABAA receptors, suggesting a functional relationship between steroid binding to VDAC-1 and modulation of GABAA receptor function. This study examines the contribution of steroid binding to VDAC proteins to modulation of GABAA receptor function and anesthesia. Photolabeling of 35-kDa protein with [3H]6-AziP was reduced 85% in brain membranes prepared from VDAC-1-deficient mice but was unaffected by deficiency of VDAC-3. The photolabeled 35-kDa protein in membranes from VDAC-1-deficient mice was identified by two-dimensional electrophoresis and electrospray ionization-tandem mass spectrometry as VDAC-2. The absence of VDAC-1 or VDAC-3 had no effect on the ability of neuroactive steroids to modulate GABAA receptor function as evidenced by radioligand ([35S] t-butylbicyclophosphorothionate) binding or by electrophysiological studies. Electrophysiological studies also showed that neuroactive steroids modulate GABAA receptor function normally in VDAC-2-deficient fibroblasts transfected with α1β2γ2 GABAA receptor subunits. Finally, the neuroactive steroid pregnanolone [(3α,5β)-3-hydroxypregnan-20-one] produced anesthesia (loss of righting reflex) in VDAC-1- and VDAC-3-deficient mice, and there was no difference in the recovery time between the VDAC-deficient mice and wild-type controls. These data indicate that neuroactive steroid binding to VDAC-1, -2, or -3 is unlikely to mediate GABAA receptor modulation or anesthesia.

Footnotes

  • This work was supported in part by National Institutes of Health Grants P01-GM47969 (to J.H.S., D.F.C., and A.S.E.), AA12952 (to S.J.M.), and R01 GM055713 (to W.J.C.), by a grant from the Klingenstein Foundation (to S.J.M.) and by the Alcoholic Beverage Medical Research Foundation (to G.A.).

  • DOI: 10.1124/jpet.103.058123.

  • ABBREVIATIONS: 6-AziP, (3α,5β)-6-azi-3-hydroxypregnan-20-one; VDAC, voltage-dependent anion channel; G418, geneticin; TBPS, t-butylbicyclophosphorothionate; ACN, (3α,5α)-3-hydroxyandrostan-20-carbonitrile; PAGE, polyacrylamide gel electrophoresis; CTβ, activation-related closing time; 3α5αP, allopregnanolone [(3α,5α)-3-hydroxypregnan-20-one]; 3α5βP, pregnanolone [(3α,5β)-3-hydroxypregnan-20-one].

    • Received August 23, 2003.
    • Accepted October 30, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleCELLULAR AND MOLECULAR

Neuroactive Steroid Interactions with Voltage-Dependent Anion Channels: Lack of Relationship to GABAA Receptor Modulation and Anesthesia

Ramin Darbandi-Tonkabon, Brad D. Manion, William R. Hastings, William J. Craigen, Gustav Akk, John R. Bracamontes, Yejun He, Tatiana V. Sheiko, Joseph H. Steinbach, Steven J. Mennerick, Douglas F. Covey and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 502-511; DOI: https://doi.org/10.1124/jpet.103.058123

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Research ArticleCELLULAR AND MOLECULAR

Neuroactive Steroid Interactions with Voltage-Dependent Anion Channels: Lack of Relationship to GABAA Receptor Modulation and Anesthesia

Ramin Darbandi-Tonkabon, Brad D. Manion, William R. Hastings, William J. Craigen, Gustav Akk, John R. Bracamontes, Yejun He, Tatiana V. Sheiko, Joseph H. Steinbach, Steven J. Mennerick, Douglas F. Covey and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 502-511; DOI: https://doi.org/10.1124/jpet.103.058123
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