Referenced in: none

Automatically associated channels: Kv11.1 , Kv11.2 , Kv11.3

Title: Structural basis for ether-a-go-go-related gene K+ channel subtype-dependent activation by niflumic acid.

Authors: David Fernandez, John Sargent, Frank B Sachse, Michael C Sanguinetti

Journal, date & volume: Mol. Pharmacol., 2008 Apr , 73, 1159-67

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18218980

Abstract
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.