TY - JOUR T1 - Structural Basis for <em>Ether-a-go-go</em>-Related Gene K<sup>+</sup> Channel Subtype-Dependent Activation by Niflumic Acid JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1159 LP - 1167 DO - 10.1124/mol.107.043505 VL - 73 IS - 4 AU - David Fernandez AU - John Sargent AU - Frank B. Sachse AU - Michael C. Sanguinetti Y1 - 2008/04/01 UR - http://molpharm.aspetjournals.org/content/73/4/1159.abstract N2 - Niflumic acid [2-((3-(trifluoromethyl)phenyl)amino)-3-pyridinecarboxylic acid, NFA] is a nonsteroidal anti-inflammatory drug that also blocks or modulates the gating of a wide spectrum of ion channels. Here we investigated the mechanism of channel activation by NFA on ether-a-go-go-related gene (ERG) K+ channel subtypes expressed in Xenopus laevis oocytes using two-electrode voltage-clamp techniques. NFA acted from the extracellular side of the membrane to differentially enhance ERG channel currents independent of channel state. At 1 mM, NFA shifted the half-point for activation by -6, -18, and -11 mV for ERG1, ERG2, and ERG3 channels, respectively. The half-point for channel inactivation was shifted by +5 to +9 mV by NFA. The structural basis for the ERG subtype-specific response to NFA was explored with chimeric channels and site-directed mutagenesis. The molecular determinants of enhanced sensitivity of ERG2 channels to NFA were isolated to an Arg and a Thr triplet in the extracellular S3-S4 linker. The American Society for Pharmacology and Experimental Therapeutics ER -