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Structural Basis for Ether-a-go-go-Related Gene K⁺ Channel Subtype-Dependent Activation by Niflumic Acid

Nora Eccles Harrison Cardiovascular Research and Training Institute and Department of Physiology, University of Utah, Salt Lake City, Utah

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.

Address correspondence to: Michael C. Sanguinetti, Nora Eccles Harrison Cardiovascular Research and Training Institute, Department of Physiology, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112. E-mail: sanguinetti{at}cvrti.utah.edu

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