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Research ArticleArticle

Novel Neuroprotective K+ Channel Inhibitor Identified by High-Throughput Screening in Yeast

Elena Zaks-Makhina, Yonjung Kim, Elias Aizenman and Edwin S. Levitan
Molecular Pharmacology January 2004, 65 (1) 214-219; DOI: https://doi.org/10.1124/mol.65.1.214
Elena Zaks-Makhina
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Yonjung Kim
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Elias Aizenman
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Edwin S. Levitan
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Abstract

Discovery of K+ channel modulators is limited by low-throughput capacity of existing K+ channel assays. To enable high-throughput screening for novel pharmacological modulators of K+ channels, we developed an assay based on growth of yeast that functionally expresses mammalian Kir2.1 channels. Screening of 10,000 small molecules from a combinatorial chemical library yielded 42 potential Kir2.1 inhibitors. One compound, 3-bicyclo[2.2.1]hept-2-yl-benzene-1,2-diol, was confirmed to inhibit K+ channels in patch-clamp measurements in mammalian cells with EC50 values of 60 and 1 μM for Kir2.1 and Kv2.1 channels, respectively. Inhibition of Kv2.1 channels decreased in the presence of the external pore blocker tetraethylammonium (TEA) and depended on a residue required for extracellular TEA action, suggesting that the identified compound targets the external mouth of the channel. Furthermore, at the nontoxic concentration of 3 μM, the identified compound completely abolished in vitro neuronal apoptosis mediated by Kv2.1 channels. Therefore, yeast-based screening has identified a novel uncharged neuroprotective mammalian K+ channel inhibitor.

  • Received August 19, 2003.
  • Accepted October 8, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (1)
Molecular Pharmacology
Vol. 65, Issue 1
1 Jan 2004
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Research ArticleArticle

Novel Neuroprotective K+ Channel Inhibitor Identified by High-Throughput Screening in Yeast

Elena Zaks-Makhina, Yonjung Kim, Elias Aizenman and Edwin S. Levitan
Molecular Pharmacology January 1, 2004, 65 (1) 214-219; DOI: https://doi.org/10.1124/mol.65.1.214

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Research ArticleArticle

Novel Neuroprotective K+ Channel Inhibitor Identified by High-Throughput Screening in Yeast

Elena Zaks-Makhina, Yonjung Kim, Elias Aizenman and Edwin S. Levitan
Molecular Pharmacology January 1, 2004, 65 (1) 214-219; DOI: https://doi.org/10.1124/mol.65.1.214
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