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Research ArticleNeuropharmacology

The Antipsychotic Drug Loxapine Is an Opener of the Sodium-Activated Potassium Channel Slack (Slo2.2)

B. Biton, S. Sethuramanujam, Kelly E. Picchione, A. Bhattacharjee, N. Khessibi, F. Chesney, C. Lanneau, O. Curet and P. Avenet
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 706-715; DOI: https://doi.org/10.1124/jpet.111.184622
B. Biton
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S. Sethuramanujam
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Kelly E. Picchione
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A. Bhattacharjee
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N. Khessibi
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F. Chesney
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C. Lanneau
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O. Curet
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P. Avenet
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Abstract

Sodium-activated potassium (KNa) channels have been suggested to set the resting potential, to modulate slow after-hyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422–428, 2005). One of the genes that encodes KNa channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165–14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 μM was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC50 = 4.4 μM and EC50 = 2.9 μM, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the single-channel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native KNa channels and to increase the rheobase of action potential. This study identifies new KNa channel pharmacological tools, which will be useful for further Slack channel investigations.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.184622.

  • ABBREVIATIONS:

    RCK
    regulator of K+ conductance
    AAS
    atomic absorption spectrometry
    LOPAC
    library of pharmacologically active compounds
    EPS
    extrapyramidal syndrome
    DRG
    dorsal root ganglion
    SN
    substantia nigra
    CHO
    Chinese hamster ovary
    DMSO
    dimethyl sulfoxide
    HEK
    human embryonic kidney
    HBSS
    Hanks' balanced salt solution
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    KNa
    sodium-activated potassium.

  • Received June 9, 2011.
  • Accepted December 12, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

Loxapine Is an Opener of Slack Channels

B. Biton, S. Sethuramanujam, Kelly E. Picchione, A. Bhattacharjee, N. Khessibi, F. Chesney, C. Lanneau, O. Curet and P. Avenet
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 706-715; DOI: https://doi.org/10.1124/jpet.111.184622

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Research ArticleNeuropharmacology

Loxapine Is an Opener of Slack Channels

B. Biton, S. Sethuramanujam, Kelly E. Picchione, A. Bhattacharjee, N. Khessibi, F. Chesney, C. Lanneau, O. Curet and P. Avenet
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 706-715; DOI: https://doi.org/10.1124/jpet.111.184622
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