%0 Journal Article
%A David Fernandez
%A John Sargent
%A Frank B. Sachse
%A Michael C. Sanguinetti
%T Structural Basis for Ether-a-go-go-Related Gene K+ Channel Subtype-Dependent Activation by Niflumic Acid
%D 2008
%R 10.1124/mol.107.043505
%J Molecular Pharmacology
%P 1159-1167
%V 73
%N 4
%X 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
%U https://molpharm.aspetjournals.org/content/molpharm/73/4/1159.full.pdf