TY - JOUR T1 - Novel Neuroprotective K<sup>+</sup> Channel Inhibitor Identified by High-Throughput Screening in Yeast JF - Molecular Pharmacology JO - Mol Pharmacol SP - 214 LP - 219 DO - 10.1124/mol.65.1.214 VL - 65 IS - 1 AU - Elena Zaks-Makhina AU - Yonjung Kim AU - Elias Aizenman AU - Edwin S. Levitan Y1 - 2004/01/01 UR - http://molpharm.aspetjournals.org/content/65/1/214.abstract N2 - 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. ER -