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Molecular Pharmacology

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Research ArticleArticle

The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not L- and P-Type, High Voltage-Activated Ca2+ Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat

Yasunori M. Nakashima, Slobodan M. Todorovic, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology September 1998, 54 (3) 559-568; DOI: https://doi.org/10.1124/mol.54.3.559
Yasunori M. Nakashima
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Slobodan M. Todorovic
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Douglas F. Covey
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Christopher J. Lingle
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Abstract

High voltage-activated (HVA) Ca2+ current (ICa) was recorded from neonatal rat hippocampal and adult rat dorsal root ganglion neurons. In both cell types, (+)-3α-hydroxy-5α-androstane-17β-carbonitrile [(+)-ACN], a neuroactive steroid, had no effect on nifedipine- (L-type) or ω-agatoxin IVA- (P-type) sensitive ICa. Selective blockade of N-type current with ω-conotoxin GVIA and of Q-type current with ω-conotoxin MVIIC indicated that (+)-ACN inhibits both N- and Q-type current components in both cell types. Current persisting after blockade of all other current components (R-type) was also sensitive to (+)-ACN. Half-blockade of (+)-ACN-sensitive HVA current occurred in the range of 3–25 μm, with N-type current somewhat more sensitive than Q- or R-type. The (+)-ACN enantiomer, (−)-ACN, and pregnanolone were somewhat less effective at inhibiting total HVA current than (+)-ACN, whereas several steroid analogs, including alfaxalone, were relatively ineffective at inhibiting total HVA current. Neither guanosine-5′-O-(2-thio)diphosphate nor guanosine-5′-O-(3-thio)triphosphate altered the ability of (+)-ACN to inhibit HVA current in dorsal root ganglion neurons, indicating that (+)-ACN acts directly on Ca2+channels. The partial selectivity exhibited by (+)-ACN among different HVA current components suggests that manipulations of steroid analogues may be a useful strategy in the generation of more selective, more potent, small-molecular-weight HVA channel blockers.

Footnotes

    • Received January 29, 1998.
    • Accepted May 18, 1998.
  • Send reprint requests to: Dr. Chris Lingle, Washington University School of Medicine, Dept. of Anesthesiology, Box 8054, St. Louis, MO 63110. E-mail:clingle{at}morpheus.wustl.edu

  • ↵1 Current affiliation: Surgical Operating Theater, Kyushu University Hospital, Fukuoka, 812-8582, Japan.

  • This work was supported by National Institutes of Health Grant GM47969 (D.F.C. and C.J.L.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (3)
Molecular Pharmacology
Vol. 54, Issue 3
1 Sep 1998
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The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not L- and P-Type, High Voltage-Activated Ca2+ Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat
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Research ArticleArticle

The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not L- and P-Type, High Voltage-Activated Ca2+ Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat

Yasunori M. Nakashima, Slobodan M. Todorovic, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology September 1, 1998, 54 (3) 559-568; DOI: https://doi.org/10.1124/mol.54.3.559

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Research ArticleArticle

The Anesthetic Steroid (+)-3α-Hydroxy-5α-androstane-17β-carbonitrile Blocks N-, Q-, and R-Type, but Not L- and P-Type, High Voltage-Activated Ca2+ Current in Hippocampal and Dorsal Root Ganglion Neurons of the Rat

Yasunori M. Nakashima, Slobodan M. Todorovic, Douglas F. Covey and Christopher J. Lingle
Molecular Pharmacology September 1, 1998, 54 (3) 559-568; DOI: https://doi.org/10.1124/mol.54.3.559
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